Epidermal Growth Factor Receptor Research Articles

Preoperative prediction of HER-2 expression status in breast cancer based on MRI radiomics model

Objective: This study aims to explore the predictive value of T2-weighted imaging (T2WI), apparent diffusion coefficient (ADC), and early-delayed phases enhanced magnetic resonance imaging (DCE-MRI) radiomics prediction model in determining human epidermal growth factor receptor 2 status in breast cancer. Methods: A retrospective study was conducted, involving 187 patients with confirmed breast cancer by postsurgical pathology at Zhenjiang First People's Hospital during January 2021 and May 2023. Immunohistochemistry or fluorescence in situ hybridization was used to determine the HER-2 status of these patients, with 48 cases classified as HER-2 positive and 139 cases as HER-2 negative. The training set was used to construct the prediction models and the validation set was used to verify the prediction models. Layers of T2WI, ADC, and early-delayed phase DCE-MRI images were used to delineate the volumeof interest and 960 radiomic features were extracted from each case using Pyradiomic. After screening and dimensionality reduction by intraclass correlation coefficient, Pearson correlation analysis, least absolute shrinkage, and selection operator, the radiomics labels were established. Logistic regression analysis was used to construct the T2WI radiomics model, ADC radiomics model, DCE-2 radiomics model, DCE-6 radiomics model, and the joint sequence radiomics model to predict the HER-2 expression status of breast cancer, respectively. Based on the clinical, pathological, and MRI image characteristics of patients, univariate and multivariate logistic regression analysis wasused to construct a clinicopathological MRI feature model. The radscore of every patient and the clinicopathological MRI features which were statistically significant after screening were used to construct a nomogram model. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of each model and the decision curve analysis wasused to evaluate the clinical usefulness. Results: The T2WI, ADC, DCE-2, DCE-6, and joint sequence radiomics models, the clinicopathological MRI feature model, and the nomogram model were successfully constructed to predict the expression status of HER-2 in breast cancer. ROC analysis showed that in the training set and validation set, the areas under the curve (AUC) of the T2WI radiomics model were 0.797 and 0.760, of the ADC radiomics model were 0.776 and 0.634, of the DCE-2 radiomics model were 0.804 and 0.759, of the DCE-6 radiomics model were 0.869 and 0.798, of the combined sequence radiomics model were 0.908 and 0.847, of the clinicopathological MRI feature model were 0.703 and 0.693, and of the nomogram model were 0.938 and 0.859, respectively. In the training set, the combined sequence radiomics model outperformed the clinicopathological features model (P＜0.001). In the training and validation sets, the nomogram outperformed the clinicopathological features model (P＜0.05). In addition, the diagnostic performance of the nomogram was better than that of the four single-modality radiomics models in the training cohort (P＜0.05) and was better than that of DCE-2 and ADC models in the validation cohort (P＜0.05). Decision curve analysis indicated that the value of individualized prediction models was higher than clinical and pathological prediction models in clinical practice. The calibration curve showed that the multimodal radiomics model had a high consistency with the actual results in predicting HER-2 expression. Conclusions: T2WI, ADC and early-delayed phase DCE-MRI imaging histology models for HER-2 expression status in breast cancer are expected to provide a non-invasive virtual pathological basis for decision-making on preoperative neoadjuvant regimens in breast cancer.

Combination of betulinic acid and EGFR-TKIs exerts synergistic anti-tumor effects against wild-type EGFR NSCLC by inducing autophagy-related cell death via EGFR signaling pathway.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.

From Rarity to Reality: Osimertinib's Promising Horizon in Treating Uncommon EGFR Mutations in Non-Small Cell Lung Cancer.

In the realm of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) therapy with tyrosine kinase inhibitors (TKIs), addressing optimal treatment for uncommon EGFR mutations like G719X in exon 18, S768I in exon 20, and L861Q in exon 21 remains a pivotal yet challenging frontier. Contrary to the well-established efficacy of EGFR-TKIs in common EGFR mutations, these uncommon alterations pose unmet medical needs due to a lack of comprehensive evidence. While afatinib, a second-generation EGFR-TKI, has received FDA approval for patients with these uncommon EGFR mutations, the approval was based on a post-hoc analysis of randomized clinical trials. Recent developments include multiple clinical trials investigating the efficacy of both second and third-generation EGFR-TKIs in patients with uncommon EGFR mutations. A noteworthy example is a prospective phase II trial of osimertinib including the landmark UNICORN study, which has shown promising results in treating uncommon EGFR mutations. Despite various reports on the efficacy of afatinib and osimertinib in treating uncommon EGFR mutations, the appropriate use of these TKIs remains unclear. This review aims to consolidate the findings from the latest clinical trials focused on uncommon EGFR mutations, outlining variations in the therapeutic efficacy of these TKIs based on the specific genetic mutation. By synthesizing these findings, we aim to guide oncologists towards more informed decisions in employing TKIs for NSCLC with uncommon EGFR mutations other than exon 20 insertion. Additionally, we explore potential treatment strategies tailored to these patient populations to address the challenges posed by these mutations.

Combination of metronomic capecitabine and letrozole in metastatic hormone receptor positive, HER2 negative breast cancer: a randomized phase II trial.

First line endocrine therapy is the gold standard for advanced estrogen receptor positive, human epidermal growth factor receptor 2 negative breast cancer. Adding CDK4/6 inhibitors has improved progression free survival. Metronomic Capecitabine has proven to be safe to combine with endocrine therapy with promising efficacy. We conducted a phase II randomized, open label, single centre clinical trial on patients with metastatic ER positive and HER 2 negative breast cancer. Eligible patients were randomized (1:1) to arm A: metronomic dose of capecitabine (500 mg/m2 BID) combined with letrozole (2.5 mg OD) or arm B: letrozole single agent. The primary endpoint was progression free survival. The study was terminated early due to poor accrual and 60 eligible patients out of the planned 204 were randomized. This clinical trial is registered on ClinicalTrials.gov (MD-127-2019, NCT04571437). Between February 2019 and April 2022, 60 patients were randomized. This is the first report of the study, after a median follow-up of 18.6 months. The median age at diagnosis was 47 years with only 41.7% of patients post-menopausal. Half of our patients had bone-only disease, 45% had visceral metastasis (liver and lung) and 63% presented with endocrine sensitive disease. The estimated median PFS for the whole population was 16.2 months. Median PFS for capecitabine arm was 17.7 months versus 14.6 months for letrozole alone (p = 0.078). Overall response rate was 70% for capecitabine/letrozole arm and 56.6% for letrozole only. Clinical benefit rate was 90% in the capecitabine/letrozole arm versus 73.3% in the letrozole arm. Overall survival data is still immature after this short follow up duration. Adverse event assessment showed acceptable all grade and high grade toxicity profile consistent with the established adverse events of both capecitabine and letrozole. Anaemia (28.3%) and hand & foot syndrome (43.8%) were significantly more common in the capecitabine/letrozole arm. Capecitabine combined with letrozole have showed a trend towards improvement in progression free survival with potential more benefit to certain sub-groups and the combination showed acceptable safety profile consistent with the established known safety profile of both letrozole and capecitabine.

Plant-Derived Anti-Human Epidermal Growth Factor Receptor 2 Antibody Suppresses Trastuzumab-Resistant Breast Cancer with Enhanced Nanoscale Binding.

Traditional monoclonal antibodies such as Trastuzumab encounter limitations when treating Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer, particularly in cases that develop resistance. This study introduces plant-derived anti-HER2 variable fragments of camelid heavy chain domain (VHH) fragment crystallizable region (Fc) KEDL(K) antibody as a potent alternative for overcoming these limitations. A variety of biophysical techniques, in vitro assays, and in vivo experiments uncover the antibody's nanoscale binding dynamics with transmembrane HER2 on living cells. Single-molecule force spectroscopy reveals the rapid formation of two robust bonds, exhibiting approximately 50 pN force resistance and bond lifetimes in the second range. The antibody demonstrates a specific affinity for HER2-positive breast cancer cells, including those that are Trastuzumab-resistant. Moreover, in immune-deficient mice, the plant-derived anti-HER2 VHH-FcK antibody exhibits superior antitumor activity, especially against tumors that are resistant to Trastuzumab. These findings underscore the plant-derived antibody's potential as an impactful immunotherapeutic strategy for treating Trastuzumab-resistant HER2-positive breast cancer.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40mg daily for 2 months, then cisplatin 75mg/m2 and pemetrexed 500mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

Potential drug targets for tumors identified through Mendelian randomization analysis.

According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR) < 0.05, results showed that S100A16 was protective protein and S100A14 was risk protein for human epidermal growth factor receptor 2-positive (HER-positive) breast cancer, phosphodiesterase 5A (PDE5A) was risk protein for colorectal cancer, and melanoma inhibitory activity (MIA) was protective protein for non-small cell lung carcinoma (NSCLC). And there was no reverse causal association between them. Colocalization analysis showed that S100A14 (PP.H4.abf = 0.920) and S100A16 (PP.H4.abf = 0.932) shared causal variation with HER-positive breast cancer, and PDE5A (PP.H4.abf = 0.857) shared causal variation with colorectal cancer (CRC). The MR results of all pQTL of PDE5A and MIA were consistent with main results. In addition, the MR results of MIA and external outcome cohort were consistent with main results. In this study, genetic predictions indicate that circulating S100 calcium binding protein A14 (S100A14) and S100 calcium binding protein A16 (S100A16) are associated with increase and decrease in the risk of HER-positive breast cancer, respectively. Circulating PDE5A is associated with increased risk of CRC, while circulating MIA is associated with decreased risk of NSCLC. These findings suggest that four proteins may serve as biomarkers for cancer prevention and as potential drug targets that could be expected for approval.

Angiopoietin-like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus.

Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.

Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer.

Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Evaluation of drug resistance for EGFR-TKIs in Lung Cancer via Multicellular lung-on-a-chip.

Drug resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a primary factor affecting their therapeutic efficacy in human non-small cell lung cancer (NSCLC). NSCLC cells can undergo epithelial-mesenchymal transition (EMT) induced by many factors in the tumour microenvironment (TME), which plays a crucial role in tumour drug resistance. In this study, a multicellular lung-on-a-chip that can realise the cell co-culture of the human non-small cell lung cancer cell line HCC827, human foetal lung fibroblasts (HFL-1), and human umbilical vein endothelial cells (HUVECs) is prepared. The TME was simulated on the chip combined with perfusion and other factors, and the drug evaluation of osimertinib was performed to explore the drug resistance mechanism of EGFR-TKIs. In the early stages, a two-dimensional static cell co-culture was achieved by microchip, and the results showed that HFL-1 cells could be transformed into cancer-associated fibroblasts (CAFs), and HCC827 cells could undergo EMT, both of which were mediated by Interleukin-6 (IL-6). Vimentin (VIM) and Alpha Skeletal Muscle Actin (a-SMA) expression of HFL-1 was upregulated, whereas E-cadherin (E-cad) expression of HCC827 was down-regulated. Further, N-cadherin (N-cad) expression of HCC827 was upregulated. In both the static cell co-culture and multicellular lung-on-a-chip, HCC827 cells with CAFs co-culture or IL-6 treatment developed resistance to osimertinib. Further use of the IL-6 antibody inhibitor tocilizumab could reverse EGFR-TKI resistance to a certain extent. Combination therapy with tocilizumab and EGFR-TKIs may provide a novel therapeutic strategy for overcoming EGFR-TKI resistance caused by EMT in NSCLC. Furthermore, the lung-on-a-chip can simulate complex TME and can be used for evaluating tumour resistance and exploring mechanisms, with the potential to become an important tool for personalised diagnosis, treatment, and biomedical research.

Management of oligometastatic and oligoprogressive epidermal growth factor receptor mutated non-small cell lung cancer patients: state of the art of a combined approach

Management of oligometastatic and oligoprogressive epidermal growth factor receptor mutated non-small cell lung cancer patients: state of the art of a combined approach

Impact of immunohistochemistry staining conditions on the incidence of human epidermal growth factor receptor 2 (HER2)-low breast cancer.

We investigated frequencies of HER2-low breast cancer (BC) (immunohistochemistry [IHC] 1+ or 2+ without gene amplification) before and after IHC conditions were modified in order to understand the impact of IHC staining conditions on frequencies of HER2-low BC. Primary BC cases diagnosed at the Yeungnam University Hospital (YUH, n = 728) or Keimyung University Dongsan Hospital (KUDH, n = 290) in 2022 were reviewed, and data on HER2 status and IHC conditions were collected (cohort 1). Both institutions used the 4B5 antibody for HER2 IHC but had different staining protocols. After modifications of the IHC conditions at both institutions, primary BC cases (YUH, n = 324 and KUDH, n = 135) diagnosed from April to July 2023 (cohort 2) were reviewed to assess any changes in the frequency of HER2 status. In cohort 1, of the 728 cases diagnosed at YUH, 556 (76.4%) were HER2-zero, 76 (10.4%) were HER2-low, and 96 (13.2%) were HER2-positive, and of the 290 cases diagnosed at KUDH, 135 (46.6%) were HER2-zero, 82 (28.3%) were HER2-low, and 73 (25.2%) were HER2-positive. Modifications in HER2 IHC staining conditions dramatically increased the frequencies of HER2-low BC in cohort 2 (YUH 38.9% and KUDH 49.6%), but they did not result in significant changes in the HER2-positive rates (YUH 15.4% and KUDH 25.2%) compared to cohort 1. In conclusion, minor modifications in HER2 IHC staining conditions significantly affected the frequency of HER2-low BC but had little impact on the HER2-positivity rate. Each pathology laboratory should verify IHC conditions using control slides (including 1+) to enable the accurate identification of HER2-low BC.

A multicentric study of radiomics and artificial intelligence analysis on contrast-enhanced mammography to identify different histotypes of breast cancer.

To evaluate the performance of radiomic analysis on contrast-enhanced mammography images to identify different histotypes of breast cancer mainly in order to predict grading, to identify hormone receptors, to discriminate human epidermal growth factor receptor 2 (HER2) and to identify luminal histotype of the breast cancer. From four Italian centers were recruited 180 malignant lesions and 68 benign lesions. However, only the malignant lesions were considered for the analysis. All patients underwent contrast-enhanced mammography in cranium caudal (CC) and medium lateral oblique (MLO) view. Considering histological findings as the ground truth, four outcomes were considered: (1) G1 + G2 vs. G3; (2) HER2 + vs. HER2 - ; (3) HR + vs. HR - ; and (4) non-luminal vs. luminal A or HR + /HER2- and luminal B or HR + /HER2 + . For multivariate analysis feature selection, balancing techniques and patter recognition approaches were considered. The univariate findings showed that the diagnostic performance is low for each outcome, while the results of the multivariate analysis showed that better performances can be obtained. In the HER2 + detection, the best performance (73% of accuracy and AUC = 0.77) was obtained using a linear regression model (LRM) with 12 features extracted by MLO view. In the HR + detection, the best performance (77% of accuracy and AUC = 0.80) was obtained using a LRM with 14 features extracted by MLO view. In grading classification, the best performance was obtained by a decision tree trained with three predictors extracted by MLO view reaching an accuracy of 82% on validation set. In the luminal versus non-luminal histotype classification, the best performance was obtained by a bagged tree trained with 15 predictors extracted by CC view reaching an accuracy of 94% on validation set. The results suggest that radiomics analysis can be effectively applied to design a tool to support physician decision making in breast cancer classification. In particular, the classification of luminal versus non-luminal histotypes can be performed with high accuracy.

Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins.

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827cells, NCI-H1975cells, and NCI-H1975-TM cells (IC50=0.009μM, 0.49μM and 3.24μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50=17.93nM, 0.25μM and 0.63μM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

Tyrosine Kinase Inhibitors in Cancers: treatment optimization - Part I.

A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase. Also, gene amplification, increased protein expression and downstream activation or bypassing of signalling pathways are commonly reported mechanisms of resistance. Improved understanding of mechanisms involved in TKI resistance has resulted in the development of new generations of targeted agents. In a race against time, the search for new, more potent and efficient drugs, and/or combinations of drugs, remains necessary as new resistance mechanisms to the latest generation of TKI emerge. This review examines the various generations of TKI approved to date and their common mechanisms of resistance, focusing on TKI targeting BCR-ABL, epidermal growth factor receptor, anaplastic lymphoma kinase and BRAF/MEK tyrosine kinases.

The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension.

Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular pathologies and IGF-binding proteins (IGFBPs) are important regulators of the bioavailability and function of IGFs. In this study, we show that circulating plasma levels of IGFBP-1, IGFBP-2 and IGFBP-3 are increased in idiopathic pulmonary arterial hypertension (IPAH) patients compared to healthy individuals. These binding proteins inhibit the IGF-1 induced IGF-1 receptor (IGF1R) phosphorylation and exhibit diverging effects on the IGF-1 induced signaling pathways in human pulmonary arterial cells (i.e. healthy as well as IPAH-hPASMCs, and healthy hPAECs). Furthermore, IGFBPs are differentially expressed in an experimental mouse model of PH. In hypoxic mouse lungs, IGFBP-1 mRNA expression is decreased whereas the mRNA for IGFBP-2 is increased. In contrast to IGFBP-1, IGFBP-2 shows vaso-constrictive properties in the murine pulmonary vasculature. Our analyses show that IGFBP-1 and IGFBP-2 exhibit diverging effects on IGF-1 signaling and display a unique IGF1R-independent kinase activation pattern in human pulmonary arterial smooth muscle cells (hPASMCs), which represent a major contributor of PAH pathobiology. Furthermore, we could show that IGFBP-2, in contrast to IGFBP-1, induces epidermal growth factor receptor (EGFR) signaling, Stat-3 activation and expression of Stat-3 target genes. Based on our results, we conclude that the IGFBP family, especially IGFBP-1, IGFBP-2 and IGFBP-3, are deregulated in PAH, that they affect IGF signaling and thereby regulate the cellular phenotype in PH.

Oncogenic composite mutations can be predicted by co-mutations and their chromosomal location.

Genetic heterogeneity in tumors can show a remarkable selectivity when two or more independent genetic events occur in the same gene. This phenomenon, called composite mutation, points toward a selective pressure, which frequently causes therapy resistance to mutation-specific drugs. Since composite mutations have been described to occur in sub-clonal populations, they are not always captured through biopsy sampling. Here, we provide a proof of concept to predict composite mutations to anticipate which patients might be at risk for sub-clonally driven therapy resistance. We found that composite mutations occur in 5% of cancer patients, mostly affecting the PIK3CA, EGFR, BRAF, and KRAS genes, which are common precision medicine targets. Furthermore, we found a strong and significant relationship between the frequencies of composite mutations with commonly co-occurring mutations in a non-composite context. We also found that co-mutations are significantly enriched on the same chromosome. These observations were independently confirmed using cell line data. Finally, we show the feasibility of predicting compositive mutations based on their co-mutations (AUC 0.62, 0.81, 0.82, and 0.91 for EGFR, PIK3CA, KRAS, and BRAF, respectively). This prediction model could help to stratify patients who are at risk of developing therapy resistance-causing mutations.

FYN as an emerging biological biomarker for prognosis and potential therapeutic target in LGG.

This study aimed to explore the expression, clinical significance, and functional mechanism of FYN in lower-grade gliomas (LGG). The mRNA and protein expression of FYN in LGG tissues were detected using databases including OncoLnc, GEPIA, and Human protein atlas (HPA). The UCSC Xena browser, TIMER, STRING and Metascape databases were used to investigate Kaplan-Meier survival curves, correlations between FYN expression and various types of immune cell infiltration, protein interaction network and possible functional mechanism. FYN expression in LGG, IDH mutation or 1p19q co-deletion subgroup was significantly higher than in corresponding control groups (p < 0.05). Patients with higher FYN expression had longer overall survival (p < 0.05). Male or no 1p19q co-deletion groups with higher FYN expression also had longer overall survival (p < 0.05). FYN expression had close correlation with infiltrating levels of cell purity, CD4+T cells, macrophages, and CD8+T cells (p < 0.05). Protein interaction network result showed correlation among FYN, SH2D1A, LCK, CAV1, SRC, CBL and PTK2. Functional enrichment analysis revealed that FYN and its related genes mainly participated in bacterial invasion of epithelial cells and natural killer cell mediated cytotoxicity. Peptidyl-tyrosine phosphorylation, negative regulation of anoikis, immune effector process, transmembrane receptor protein tyrosine kinase signaling pathway, epidermal growth factor receptor signaling pathway, and negative regulation of protein modification process may be the critical biological process. FYN is up-expressed in LGG and related to its good prognosis. It participated in tumor pathophysiological processes and may be a therapeutic target for LGG.

Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p≤.05. Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p<.001), hormone receptor-positive (p<.001), and node-positive (p=.003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p<.001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p=.014) and TN and luminal A-like in HER2-0 (p=.019) showed the worst DFS. In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

RPGRIP1L as a new biomarker for prognosis and tumor immune of breast cancer.

The Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) gene encodes an important protein that performs various physiological functions. Variants of RPGRIP1L are related to a number of diseases. However, it is currently unknown whether RPGRIP1L is correlated with breast invasive carcinoma (BRCA). In BRCA tissue specimens, the expression of RPGRIP1L was found to be elevated in comparison to its levels in normal breast tissue. A notable decline in survival rates was associated with patients exhibiting heightened RPGRIP1L gene expression. Consistent with these findings, our data also show the above results. Furthermore, elevated expression of RPGRIP1L corresponded with a spectrum of unfavorable clinicopathological features, including the presence of human epidermal growth factor receptor 2 (HER2) positive, estrogen receptor (ER) positive, over 60 years old, T2, N0, and N3. At the same time, our research indicated that 50 genes and 15 proteins were positively related to RPGRIP1L, and that these proteins and genes were mostly involved in T cell proliferation, immune response, cytokine activity, and metabolic regulation. In addition, in the present study, there was a significant correlation between RPGRIP1L expression and immune cell infiltration. Finally, we found that four Chemicals could downregulate the expression of RPGRIP1L. Altogether, our results strongly indicated that RPGRIP1L might serve as a new prognostic biomarker for BRCA.