Epidermal Growth Factor Receptor Inhibitors Research Articles

Neratinib plus dasatinib is highly synergistic in HER2-positive breast cancer in vitro and in vivo

BackgroundHER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib. MethodsNeratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). In vivo efficacy was examined using orthotopically-implanted HCC1954 cells. ResultsSynergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. In vivo, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts. ConclusionsThis study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.

Cholangiocyte ciliary defects induce sustained epidermal growth factor receptor signaling.

The primary cilium, an organelle that protrudes from cell surfaces, is essential for sensing extracellular signals. With disturbed cellular communication and chronic liver pathologies, this organelle's dysfunctions have been linked to disorders, including polycystic liver disease (PLD) and Cholangiocarcinoma (CCA). The goal of this study was to elucidate the relationship between primary cilia and the crucial regulator of cellular proliferation, the epidermal growth factor receptor (EGFR) signaling pathway, which has been associated with various clinical conditions. The study identified aberrant EGFR signaling pathways in cholangiocytes lacking functional primary cilia. Using liver-specific IFT88 knockout mice, a Pkhd1 mutant rat model, and human cell lines that didn't have functional cilia. Cilia-deficient cholangiocytes showed persistent EGFR activation because of impaired receptor degradation, in contrast to their normal counterparts, where EGFR localization to the cilia promotes appropriate signaling. Using HDAC6 inhibitors to restore primary cilia accelerates EGFR degradation, thereby reducing maladaptive signaling. Importantly, experimental intervention with the HDAC6 inhibitor tubastatin A in an orthotopic rat model moved EGFR to cilia and reduced ERK phosphorylation. Concurrent administration of EGFR and HDAC6 inhibitors in cholangiocarcinoma and polycystic liver disease cells demonstrated synergistic anti-proliferative effects, which were associated with the restoration of functioning primary cilia. This study's findings shed light on ciliary function and robust EGFR signaling with slower receptor turnover. We could use therapies that restore the function of primary cilia to treat EGFR-driven diseases in PLD and CCA.

Synthesis, breast cancer activity, molecular docking and dynamic simulation of 1,4-Dihydropyridine derivatives

Breast cancer (BC) is the most prevalent cancer diagnosed in women, accounting for more than 1 in 10 new cancer diagnoses each year. Even though chemotherapy is successful in BC treatments, resistance to spreading these medications requires a new therapy. A new 1,4-Dihydropyridine (ZL1-6) series was synthesized and characterized using spectroscopic techniques such as FT-IR, 1H-NMR, 13C-NMR, and mass spectroscopy. The efficacy of these compounds against MFC7 breast cancer cells was assessed through a combination of in vitro, molecular docking, molecular dynamics, and MM-GBSA analyses. Notably, compound ZL4 exhibited promising activity against MFC7 cells (IC50 = 93.09 μg/ml), with a docking core of -6.728 kcal/mol and an MM-GBSA of -47.82 kcal/mol potentially involving the inhibition of EGFR as a mechanism of action. It is worth mentioning that these compounds were inactive against both E. Coli and S. Aureus wild strains. These findings provide a foundation for the development of innovative treatments for breast cancer.

Kurarinol restrains non-alcoholic fatty liver disease-associated hepatocellular carcinoma (HCC) progression by suppressing EGFR signaling

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a key factor for hepatocellular carcinoma (HCC) development. As a metabolic hepatic damage, there is still a lack of efficient therapy for NAFLD-HCC. Kurarinol (KUR) is a flavanone extracted from the root of Sophora flavescens, and exerts excellent hepatoprotective and lipid-lowering activities. But its potential on NAFLD-HCC still remains unclear, and thus was explored in our present study. Firstly, in vitro experiments revealed that KUR treatments markedly reduced lipid deposition and inflammatory response in hepatocytes under palmitate and oleic acid stimulation (PO) with decreased expression levels of fatty acid synthesis markers including fatty acid synthase (FASN), stearoyl-CoA desaturase-1 (SCD1) and sterol receptor element binding protein-1 (SREBP-1). Importantly, the proliferation of HCC cell lines was strongly limited by KUR in a dose-dependent manner. Of note, PO stimulation accelerated the proliferative capacity of HCC cells, whereas being significantly suppressed by KUR. Mechanistically, we found that epidermal growth factor receptor (EGFR) and its phosphorylation protein expression levels were highly down-regulated in hepatocytes and HCC cell lines under PO stimuli. More importantly, the functions of KUR to restrain lipid accumulation and HCC cell proliferation were diminished upon EGFR overexpression, confirming that EGFR suppression was necessary for KUR to treat NAFLD-HCC. Murine mouse models were finally established by the use of diethylnitrosamine (DEN) with high-fat/high-cholesterol diet (HFHC) feeding to determine the role of KUR in NAFLD-HCC. Oral gavage of KUR efficiently suppressed NAFLD-HCC formation in mice, as evidenced by the decreased tumor number and loading. KUR also ameliorated lipid accumulation, liver dysfunction, fibrosis and HCC cell proliferation in DEN/HFHC-challenged mice, along with decreased EGFR expression. Collectively, KUR may be an effective strategy for NAFLD-HCC prevention via EGFR signaling suppression.

Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer.

Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated with a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.

BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer

BackgroundImmune checkpoint inhibitors (ICIs) are the guideline endorsed first choice for patients with deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) mCRC, however a significant proportion experience primary or secondary resistance. BRAF V600E mutated (BRAFm) and dMMR/MSI-H mCRC can be treated with BRAF + EGFR inhibitors but specific data on the efficacy after progression to ICIs are missing. MethodsWe collected consecutive patients with BRAFm dMMR/MSI-H mCRC treated from 2017 to 2024 with a combination of BRAFi+EGFRi+/-MEKi, after disease progression on ICIs. A control cohort of BRAFm pMMR/MSS mCRC patients treated with encorafenib+cetuximab+/-binimetinib from 2nd line was used. ResultsdMMR/MSI-H (n = 50) BRAFm mCRC patients were more often > 70-year-old, with right-sided primary tumors, without liver but more lymphnode metastases than pMMR/MSS (n = 170). They were treated more frequently beyond 2nd line and 45 % were primary progressors to ICIs. Lower ORR (18 % versus 32 %, p = 0.09) and DCR (60 % versus 73 %, p = 0.11) was seen without reaching significance in dMMR/MSI-H as compared to pMMR/MSS patients. After a median follow-up of 14.04 months, no differences in PFS (median 5.13 versus 4.50 months, HR 0.83, 95 %CI: 0.57–1.20, p = 0.31) and OS (median 10.75 versus 9.11 months, HR 0.89, 95 %CI: 0.59–1.32, p = 0.55) were observed. ConclusionsOur results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.

The Mutational and Microenvironmental Landscape of Cutaneous Squamous Cell Carcinoma: A Review.

Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. Despite this, several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR. In addition to mutations, the tumor microenvironment and the manipulation and evasion of the immune system play a critical role in cSCC progression. Novel therapeutic approaches, such as immunotherapy and EGFR inhibitors, have been used to target these dysregulations, and have shown promise in treating advanced cSCC cases, emphasizing the need for targeted interventions considering both genetic and microenvironmental factors for improved patient outcomes.

Evolutionary dependency of cancer mutations in gene pairs inferred by nonsynonymous-synonymous mutation ratios

BackgroundDetermining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other.MethodsWe employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity.ResultsWe propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively.ConclusionsWe propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications.

Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation

ObjectivesHepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. MethodsWe examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre + Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. ResultsLratCre + Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HSCs. This was inhibited by nicotinic acid treatment which blunted the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. ConclusionsLoss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.

A linear and reticulate crusted keratotic papulopustular eruption: a rare presentation of PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, and Dryness due to Epidermal growth factor receptor inhibitors) complex.

A linear and reticulate crusted keratotic papulopustular eruption: a rare presentation of PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, and Dryness due to Epidermal growth factor receptor inhibitors) complex.

Pembrolizumab plus cetuximab with neoadjuvant chemotherapy for head and neck squamous cell carcinoma.

Head and neck cancer cells commonly express programmed death ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR), both of which play pivotal roles in the antitumor cellular immune response. Pembrolizumab, a PD-1 inhibitor, and cetuximab, an EGFR inhibitor, are typically effective agents combined with neoadjuvant platinum-based chemotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC). This study aims to evaluate the efficacy and safety of neoadjuvant immunochemotherapy in patients with HNSCC. Patients with HNSCC underwent radical surgery and complete cervical lymph node dissection following neoadjuvant immunochemotherapy at RenJi Hospital from January 2021 to June 2024 were retrospectively analyzed. The primary endpoint was major pathological response (MPR). We further explored the relationship between the efficacy and immune estimators. Twenty-one patients were enrolled in this retrospective study. The MPR was 66.7%, including 11 patients who achieved a pathological complete response (pCR). The overall response rate (ORR) was 90.5%, and the complete response (CR) rate was 28.6%. The oropharynx, as the primary site, was the sensitive tumor type to neoadjuvant immunochemotherapy. The most common adverse event (AEs) was anemia (61.9%). No grade 4 AE or delayed surgery was reported. Laryngeal preservation rates were 90.9% (10/11), and pathological findings confirmed negative surgical margins for all patients. Moreover, pre-treatment peripheral lymphocyte count, monocyte count, and platelet to lymphocyte ratio (PLR) displayed a significant correlation with the treatment response. Pembrolizumab plus cetuximab with chemotherapy for patients with HNSCC is a feasible and safe clinical protocol fulfilling organ preservation and life quality improvement. Pre-treatment peripheral immune estimators could help to screen patients who may respond to the neoadjuvant immunochemotherapy.

Ocular surface adverse reactions of antitumor-targeted drugs

With the extensive application of targeted drugs, the survival rate of cancer patients has been significantly improved. However, adverse reactions to the drugs have also become apparent, especially those affecting the ocular surface, which can severely impact patients' vision and quality of life. The article systematically analyzes a variety of targeted drugs, including epidermal growth factor receptor inhibitors, human epidermal growth factor receptor 2 inhibitors, fibroblast growth factor receptor inhibitors, selective estrogen receptor modulators, vascular endothelial growth factor receptor inhibitors, aromatase inhibitors, proteasome inhibitors, antibody-drug conjugates, Bruton's tyrosine kinase inhibitors, FMS-like tyrosine kinase 3 inhibitors, and cyclin-dependent kinase inhibitors, and discusses their adverse reactions on the ocular surface. The review emphasizes the role of clinicians in monitoring and managing patients' ocular surface health and the importance of early diagnosis and intervention to ensure that patients receive optimal visual protection while undergoing antitumor treatment.

Functional loss of ERBB receptor feedback inhibitor 1 (MIG6) promotes glioblastoma tumorigenesis by aberrantactivation of epidermal growth factor receptor (EGFR).

Dysregulation of epidermal growth factor receptor (EGFR) is one of the most common mechanisms associated with the pathogenesis of various cancers. Mitogen-inducible gene 6 [MIG6; also known as ERBB receptor feedback inhibitor 1 (ERRFI1)], identified as a feedback inhibitor of EGFR, negatively regulates EGFR by directly inhibiting its kinase activity and facilitating its internalization, subsequently leading to degradation. Despite its proposed role as an EGFR-dependent tumor suppressor, the functional consequences and clinical relevance in cancer etiology remain incompletely understood. Here, we identify that the stoichiometric balance between MIG6 and EGFR is crucial in promoting EGFR-dependent oncogenic growth in various experimental model systems. In addition, a subset of ERRFI1 (the official gene symbol of MIG6) mutations exhibit impaired ability to suppress the enzymatic activation of EGFR at multiple levels. In summary, our data suggest that decreased or loss of MIG6 activity can lead to abnormal activation of EGFR, potentially contributing to cellular transformation. We propose that the mutation status of ERRFI1 and the expression levels of MIG6 can serve as additional biomarkers for guiding EGFR-targeted cancer therapies, including glioblastoma.

REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations.

TPS219 Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations or other uncommon single/compound EGFR mutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Patients randomized to chemotherapy alone will be allowed to cross over to zipalertinib monotherapy after documented progressive disease. The primary endpoint in Part B is progression-free survival assessed by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 260 patients. Enrollment started in June 2023. Clinical trial information: NCT05973773 .

Design, synthesis and bioevaluation of dual EGFR-PI3Kα inhibitors for potential treatment of NSCLC

Aberrant activation or mutation of the EGFR-PI3K-Akt-mTOR signaling pathway has been implicated in a wide range of human cancers, especially non-small-cell lung cancer (NSCLC). Thus, dual inhibition of EGFR and PI3K has been investigated as a promising strategy to address acquired drug resistance resulting from the use of tyrosine kinase inhibitors. A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. The optimal compound 30k showed potent kinase inhibitory activities with IC50 values of 3.6 and 30.0 nM against EGFRL858R/T790M and PI3Kα, respectively. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.

Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication.

Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and epidermal growth factor receptor (EGFR), which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both kinases with clinically available agents, this study aimed to assess the antitumor efficacy of both pharmacologic and genetic SYK and EGFR co-inhibition using a multifaceted approach to analyze the global phosphoproteome and chemoresistant ovarian cancer cell lines, patient-derived organoids, and xenograft models. Dual inhibition of SYK and EGFR in chemoresistant ovarian cancer cells elicited a highly synergistic antitumor effect. Notably, the combined inhibition strategy activated the DNA damage response, induced G1 cell cycle arrest, and promoted apoptosis. The phosphoproteomic analysis revealed that perturbation of SYK and EGFR signaling induced a significant reduction in both phosphorylated and total protein levels of cell division cycle 6 (CDC6), a crucial initiator of DNA replication. Together, this study offers preclinical evidence supporting dual inhibition of SYK and EGFR as a promising treatment for chemoresistant ovarian cancer that disrupts DNA synthesis by impairing formation of the prereplication complex. These findings warrant further clinical investigation to explore the potential of this combination therapy in overcoming drug resistance and improving patient outcomes.

Kinetic Trajectories of Glucose Uptake in Single Cancer Cells Reveal a Drug-Induced Cell-State Change Within Hours of Drug Treatment.

The development of drug resistance is a nearly universal phenomenon in patients with glioblastoma multiforme (GBM) brain tumors. Upon treatment, GBM cancer cells may initially undergo a drug-induced cell-state change to a drug-tolerant, slow-cycling state. The kinetics of that process are not well understood, in part due to the heterogeneity of GBM tumors and tumor models, which can confound the interpretation of kinetic data. Here, we resolve drug-adaptation kinetics in a patient-derived in vitro GBM tumor model characterized by the epithelial growth factor receptor (EGFR) variant(v)III oncogene treated with an EGFR inhibitor. We use radiolabeled 18F-fluorodeoxyglucose (FDG) to monitor the glucose uptake trajectories of single GBM cancer cells over a 12 h period of drug treatment. Autocorrelation analysis of the single-cell glucose uptake trajectories reveals evidence of a drug-induced cell-state change from a high- to low-glycolytic phenotype after 5-7 h of drug treatment. Information theoretic analysis of a bulk transcriptome kinetic series of the GBM tumor model delineated the underlying molecular mechanisms driving the cellular state change, including a shift from a stem-like mesenchymal state to a more differentiated, slow-cycling astrocyte-like state. Our results demonstrate that complex drug-induced cancer cell-state changes of cancer cells can be captured via measurements of single cell metabolic trajectories and reveal the extremely facile nature of drug adaptation.

Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.

Molecular Modeling of some 1,3,4-Oxadiazole Derivatives as EGFR Inhibitors for the Treatment of Cancer

Background: Cancer is a group of illnesses characterised by the impartial increase and unfolding of somatic cells. A variety of natural compounds, such as curcumin, zingiberine and their composites, and synthetic organic derivatives of imidazole, benzothiazole, oxadiazole, quinazoline etc., have been developed as anticancer agents. But many of these show various side effects, drug resilience, and toxicity to the normal cells of the host body. Therefore, there is still demand to develop new synthetic derivatives to improve their pharmacological profile. Objective: The Aim of this study is to understand the binding mode and to check the drug likeliness of numerous 1,3,4-oxadiazole derivatives as EGFR inhibitors for the treatment of cancer. The objective of the study is to screen newly designed derivatives of 1,3,4-oxadiazole using molecular docking and ADMET studies as EGFR inhibitors. Methods: In silico docking studies were performed using AutoDockVina software, and compounds were further studied for ADME and toxicity using SwissADME and pkCSM software, respectively. Results: Considering the docking results, pharmacokinetic behaviour and toxicity profile, eight derivatives (derivatives 2,3,4,5,10,13,16, and 17) showed potential as EGFR inhibitors. Conclusion: Compounds 2 and 3 showed the highest binding affinity in the pocket of EGFR and also displayed a better pharmacokinetic profile. Therefore, these derivatives can be used in the management of cancer and can be taken further for wet-lab studies.

Design, Synthesis and Cytotoxic Studies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer

Background: The pre-existing EGFR (Epidermal Growth Factor Receptors) inhibitors (Gefitinib, Afatinib and osimertinib) show significant resistance after one year of EGFR therapy in NSCLC (Non-small cell lung cancer) patients. With the aim of overcoming the resistance problem associated with a current therapeutic regimen, there is an imperative need for the development of novel 4- anilinoquinazoline derivatives that are specifically designed for resistance cases of NSCLC patients. Objective: We designed and synthesized eighteen 4-anilinoquinazolines derivatives as a novel scaffold and evaluated their anti-cancer potential against different NSCLC cell lines. Methods: Molecular docking study of designed compounds were performed on Glide v5.8 (Schrodinger, LLC, New York, NY). Synthesis of 4-anilinoquinazoline derivatives were performed, based on the docking score and was characterized by various spectroscopic methods. Further, in vitro anti-cancer activity was performed using MTT assay on different cancer cell lines. Results: Molecular docking analysis [EGFRT790M mutant (4I22)] indicated that most of these analogs (6g, 6j, 6l, 6m and 6o) were found to be higher docking scores than gefitinib. Furthermore, spectral analysis revealed that the designed compounds were synthesized successfully. The compounds 6a, 6d, 6g, 6i, 6j and 6m were identified as the potent inhibitors against (A431, H1975, A549) cell lines as compared to reference standard gefitinib. Excitingly, compound 6j (with IC50 values of 4.88 ± 0.13, 4.38 ± 0.08 & 11.97 ± 0.14 μM) was identified as the most potent inhibitor for (A431, H1975, A549) cell lines. Conclusion: The study suggested that the six derivatives showed significant therapeutic potential against different NSCLC cell lines as compared to reference standard gefitinib.