Epidermal Growth Factor Receptor-targeted Therapy Research Articles

Genome-scale CRISPR-Cas9 screen identifies PAICS as a therapeutic target for EGFR wild-type non-small cell lung cancer.

Epidermal growth factor receptor-targeted (EGFR-targeted) therapies show promise for non-small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild-type NSCLC. A genome-wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild-type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild-type NSCLC cells. Additionally, PAICS silencing led to cell-cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild-type NSCLC. PAICS silencing also caused DNA damage and cell-cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K-AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild-type NSCLC and represents a potential therapeutic target for this disease.

Retracted: Magnetic Resonance Imaging Features in Diagnosis of Breast Cancer and Evaluation of Effect of Epidermal Growth Factor Receptor-Targeted Therapy.

[This retracts the article DOI: 10.1155/2022/3127058.].

An individual patient-level meta-analysis of non–small-cell lung cancer leptomeningeal metastases treated with epidermal growth factor receptor inhibitors.

e21118 Background: Leptomeningeal metastasis (LM) is a debilitating condition associated with advanced non-small cell lung cancer (NSCLC). When driver mutations in the epidermal growth factor receptor (EGFR) are identified, targeted therapies (TT) represent an appealing therapeutic strategy. However, the efficacy of TT for LM is unknown as LM patients are routinely omitted from clinical trials. Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of EGFR TT in EGFR-mutant NSCLC LM in accordance with PRISMA guidelines. EGFR-TTs evaluated were erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, zorifertinib, and furmonertinib. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). To assess differences between groups, shared frailty Cox regression models were used to estimate the hazard ratio (HR), 95% confidence interval (CI) and p-value. Results: 7780 abstracts were screened, identifying 126 publications with 232 patients, corresponding to 272 lines of EGFR-TT for NSCLC LM which met inclusion criteria. The overall median PFS (mPFS) in patients receiving any EGFR-TT was 9.15 months and the median overall survival was 14.5 months. In univariable analyses, osimertinib was associated prolonged PFS compared to other EGFR-TT, (mPFS of 11 versus 8 months, HR = 0.64; 95% CI: 0.44-0.93; P = 0.02). Osimertinib was numerically associated with prolonged OS compared to other EGFR-TT (mOS 16.8 months versus 13.6 months, HR = 0.72; 95% CI 0.44-1.17, P = 0.188). In multivariable analyses, ECOG performance status > 2 was independently associated with shortened PFS (mPFS 10 versus 8 months, HR = 1.54, 95% CI: 1.26-3.04; P < 0.05) and OS (mOS 16.5 versus 10 months, HR = 3.33, 95% CI: 1.80-6.18; P < 0.05). Conclusions: In the largest cohort of NSCLC LM treated with EGFR TT compiled to date, osimertinib is associated with marginally improved outcomes compared to other EGFR TTs. ECOG performance status is an independent predictor of prognosis in these patients. These results highlight the need for prospective studies for this difficult to treat patient population.

Significant metabolic alterations in non-small cell lung cancer patients by epidermal growth factor receptor-targeted therapy and PD-1/PD-L1 immunotherapy.

Background: Cancer-related deaths are primarily attributable to lung cancer, of which non-small cell lung cancer (NSCLC) is the most common type. Molecular targeting therapy and antitumor immunotherapy have both made great strides in the treatment of NSCLC, but their underlying mechanisms remain unclear, especially from a metabolic perspective. Methods: Herein, we used a nontargeted metabolomics approach based on liquid chromatography-mass spectrometry to analyze the metabolic response of NSCLC patients to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) or PD-1/PD-L1 inhibitors. Multiple analyses, including principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) and pathway analysis, were used for metabolic data analysis. Additionally, differential metabolites were analysed and identified by publically available and integrated databases. Results: After treatment with EGFR-TKIs or PD-1/PD-L1 inhibitors, glutamate/glutamine, phenylalanine, n-acetyl-l-leucine, n-acetyl-d-tryptophan, D-n-valine, arachidonic acid, and linoleic acid levels were significantly increased in patients with NSCLC, whereas carnitine, stearyl carnitine, palmitoyl carnitine, linoleic carnitine, and palmitic acid levels were markedly decreased. Compared with newly diagnosed, untreated patients, there were three shared metabolic pathways (phenylalanine metabolism, glycerophospholipid metabolism, and D-glutamine and D-glutamate metabolism) in the EGFR-TKIs or PD-1/PD-L1 inhibitor-treated groups, all of which were related to lipid and amino acid metabolism. Moreover, there were significant differences in lipid metabolism (glycerophospholipid metabolism and phosphatidylinositol signaling) and amino acid metabolism (tryptophan metabolism) between the EGFR-TKI and PD-1/PD-L1 inhibitor groups. Conclusion: Our results show that EGFR-TKIs and PD-1/PD-L1 inhibitors induce changes in carnitine, amino acids, fatty acids, and lipids and alter related metabolic pathways in NSCLC patients. Endogenous metabolism changes occur due to drug action and might be indicative of antitumor therapeutic effect. These findings will provide new clues for identifying the antitumor mechanism of these two treatments from the perspective of metabolism.

Magnetic Resonance Imaging Features in Diagnosis of Breast Cancer and Evaluation of Effect of Epidermal Growth Factor Receptor-Targeted Therapy.

Breast cancer diagnosis and treatment are important healthcare issues in the Industrialized World. In this study, magnetic resonance imaging (MRI) images are used to diagnose breast cancer (BC) and analyze the application effect of epidermal factor receptor-targeted therapy in the treatment of BC. A total of 858 patients diagnosed with BC in Jincheng People's Hospital from 2019 to 2021 are included and randomly divided into an experimental group and a control group. The experimental group is treated with epidermal growth factor receptor- (EGFR-) targeted therapy, and the control group is treated with conventional chemotherapy according to subsequent treatment modalities. Experimental results show that compared with manual segmentation, machine automatic segmentation includes the local and edge information of the image with higher accuracy, compared with benign and malignant tumors. There are significant differences in the changes of Tpeak, SSmax, El, E2, and E5, P < 0.05, with SSmax and El having the greatest changes. After chemotherapy, the recorded maximum diameter of cancer foci in the control and the experimental groups are 26.4 ± 11.6 mm and 20.3 ± 13.5 mm, respectively, and the difference is statistically meaningful (P < 0.05). The ADC value (12.74 ± 2.08) in the experimental group is higher than that (9.7 ± 1.88) in the control group (P < 0.05). There is a significant difference in SSmax between the control group and experimental group (P < 0.05), the SImax, pH values of the control group are significantly higher than those of the experimental group (P < 0.05), and the SSmaxR value (7.82 ± 6.24) in the experimental group is lower than that in the control group (10.08 ± 6.25), but the difference is not significant, P > 0.05. The proposed MRI method has high sensitivity and accuracy in the diagnosis of BC, improving the detection rate of lesions, compared with conventional chemotherapy. In addition, epidermal factor receptor-targeted therapy has a better therapeutic effect, with significant changes in cancer foci, which has the value of clinical promotion.

Cancer therapy-related cardiac dysfunction: is endothelial dysfunction at the heart of the matter?

Significant improvements in cancer survival have brought to light unintended long-term adverse cardiovascular effects associated with cancer treatment. Although capable of manifesting a broad range of cardiovascular complications, cancer therapy-related cardiac dysfunction (CTRCD) remains particularly common among the mainstay anthracycline-based and human epidermal growth factor receptor-targeted therapies. Unfortunately, the early asymptomatic stages of CTRCD are difficult to detect by cardiac imaging alone, and the initiating mechanisms remain incompletely understood. More recently, circulating inflammatory markers, cardiac biomarkers, microRNAs, and extracellular vesicles (EVs) have been considered as early markers of cardiovascular injury. Concomitantly, the role of the endothelium in regulating cardiac function in the context of CTRCD is starting to be understood. In this review, we highlight the impact of breast cancer therapies on the cardiovascular system with a focus on the endothelium, and examine the status of circulating biomarkers, including inflammatory markers, cardiac biomarkers, microRNAs, and endothelial cell-derived EVs. Investigation of these emerging biomarkers may uncover mechanisms of injury, detect early stages of cardiovascular damage, and elucidate novel therapeutic approaches.

ADENOCARCINOMA OF THE LUNG WITH A MILIARY PATTERN

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: A miliary pattern on chest imaging is often concerning for primary tuberculosis. However, such nodules may also be seen in fungal infections and autoimmune or (rarely) metastatic processes. Here, we report a case of a miliary mottling on chest imaging associated with metastatic lung adenocarcinoma. CASE PRESENTATION: A 39-year-old man with a history of obesity and tobacco use presented with worsening chest congestion and dyspnea on exertion for 2 months. He had occasional wheezing without associated symptoms, including fever, chills or night sweats, or weight loss. He worked in environmental services without any known sick contacts or recent travel history. Physical examination was unremarkable except a small, palpable right supraclavicular lymph node. The initial chest x-ray showed diffuse interstitial infiltrates. Chest CT revealed innumerable bilateral cavitary nodules with an apical gradient, a right lower lobe 6-cm mass with cavitation, and mediastinal and supraclavicular lymphadenopathy. Given concern of pulmonary tuberculosis with a miliary component, the patient remained on airborne precautions. Laboratory workup was notable for a mild leukocytosis of 12,000. Sputum cultures and AFB staining were negative. A baseline connective tissue panel, AFP, and beta-hCG levels were unmeasurable. Given his age and concern for metastatic disease, a scrotal ultrasound was performed but did not reveal any testicular mass. Subsequently, the patient underwent a fine-needle aspiration and core biopsy of the right supraclavicular lymph node, which showed metastatic adenocarcinoma. The immunohistochemical profile was suggestive of a positive CK7 but negative for CK20, TTF-1, CDX2, and Napsin A---support the diagnosis of non-small cell lung cancer with a KRAS Q61K mutation. Immuno-chemotherapy with a combination of carboplatin, pemetrexed, and pembrolizumab was initiated, given his stage IV metastatic lung adenocarcinoma. DISCUSSION: The differential diagnosis for miliary patterns on chest imaging includes tuberculosis, fungal infections, sarcoidosis, pneumoconiosis, and secondary metastasis. Miliary-pattern metastatic lung adenocarcinomas have been rarely reported. Our case is of interest given the negative TTF-1 with a KRAS Q61K mutation, the later of which is associated with resistance to the EGFR inhibitors gefitinib and erlotinib. This entity is thought to have a poorer prognosis than KRAS wild-type adenocarcinomas. CONCLUSIONS: The initial radiologic presentation of these cases can be misleading in areas with high prevalence of infections such as tuberculosis and fungal infections. The possibility of primary lung cancer should also be considered in these cases. Reference #1: A. Sekine et al., “Miliary lung metastases from non‑small cell lung cancer with Exon 20 insertion: A dismal prognostic entity: A case report,” Mol. Clin. Oncol., Oct. 2018, doi: 10.3892/mco.2018.1730. Reference #2: L. Kimmig and J. Bueno, “Miliary Nodules: Not Always Tuberculosis,” Ann. Am. Thorac. Soc., vol. 14, no. 12, pp. 1858–1860, Dec. 2017, doi: 10.1513/AnnalsATS.201706-436CC. Reference #3: P. J. Roberts, T. E. Stinchcombe, C. J. Der, and M. A. Socinski, “Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy?,” J. Clin. Oncol., vol. 28, no. 31, pp. 4769–77, Nov. 2010, doi: 10.1200/JCO.2009.27.4365. DISCLOSURES: No relevant relationships by Kamran Manzoor, source=Web Response No relevant relationships by Eric Robbins, source=Web Response No relevant relationships by Ajit Thota, source=Web Response

Low paravertebral muscle mass in patients with bone metastases from lung cancer is associated with poor prognosis.

Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.

Targeting EGFR of triple-negative breast cancer enhances the therapeutic efficacy of paclitaxel- and cetuximab-conjugated nanodiamond nanocomposite

Breast cancer is the most common malignancy and a leading cause of cancer-related mortality among women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). However, epidermal growth factor receptor (EGFR) is highly expressed in most of the TNBCs, which may provide a potential target for EGFR targeting therapy. Nanodiamond (ND) is a carbon-based nanomaterial with several advantages, including fluorescence emission, biocompatibility, and drug delivery applications. In this study, we designed a nanocomposite by using ND conjugated with paclitaxel (PTX) and cetuximab (Cet) for targeting therapy on the EGFR-positive TNBC cells. ND-PTX inhibited cell viability and induced mitotic catastrophe in various human breast cancer cell lines (MDA-MB-231, MCF-7, and BT474); in contrast, ND alone did not induce cell death. ND-PTX inhibited the xenografted human breast tumors in nude mice. We further investigated ND-PTX-Cet drug efficacy on the TNBC of MDA-MB-231 breast cancer cells. ND-PTX-Cet could specifically bind to EGFR and enhanced the anticancer effects including drug uptake levels, mitotic catastrophe, and apoptosis in the EGFR-expressed MDA-MB-231 cells but not in the EGFR-negative MCF-7 cells. In addition, ND-PTX-Cet increased the protein levels of active caspase-3 and phospho-histone H3 (Ser10). Furthermore, ND-PTX-Cet showed more effective on the reduction of TNBC tumor volume by comparison with ND-PTX. Taken together, these results demonstrated that ND-PTX-Cet nanocomposite enhanced mitotic catastrophe and apoptosis by targeting EGFR of TNBC cells, which can provide a feasible strategy for TNBC therapy. Statement of significanceCurrent TNBC treatment is ineffective against the survival rate of TNBC patients. Therefore, the development of new treatment strategies for TNBC patients is urgently needed. Here, we have designed a nanocomposite by targeting on the EGFR of TNBC to enhance therapeutic efficacy by ND-conjugated PTX and Cet (ND-PTX-Cet). Interestingly, we found that the co-delivery of Cet and PTX by ND enhanced the apoptosis, mitotic catastrophe and tumor inhibition in the EGFR-expressed TNBC in vitro and in vivo. Consequently, this nanocomposite ND-PTX-Cet can be applied for targeting EGFR of human TNBC therapy.

Development of a SPECT Tracer to Image c-Met Expression in a Xenograft Model of Non-Small Cell Lung Cancer.

Elevated expression of the c-Met receptor plays a crucial role in cancers. In non-small cell lung cancer (NSCLC), aberrant activation of the c-Met signaling pathway contributes to tumorigenesis and cancer progression and may mediate acquired resistance to epidermal growth factor receptor-targeted therapy. c-Met is therefore emerging as a promising therapeutic target for NSCLC, and methods for noninvasive in vivo assessment of c-Met expression would improve NSCLC treatment and diagnosis. Methods: We developed a new c-Met-binding peptide (cMBP) radiotracer, 99mTc-hydrazine nicotinamide (HYNIC)-cMBP, for SPECT imaging. Cell uptake assays were performed on 2 NSCLC cell lines with different c-Met expressions: H1993 (high expression) and H1299 (no expression). In vivo tumor specificity was assessed by SPECT imaging in tumor-bearing mice at 0.5, 1, 2, and 4 h after injection of the probe. Blocking assays, biodistribution, and autoradiography were also conducted to determine probe specificity. Results:99mTc-HYNIC-cMBP was prepared with high efficiency and showed higher uptake in H1993 cells than in H1299 cells. Biodistribution and autoradiography also showed significantly higher percentages of the injected dose for 99mTc-HYNIC-cMBP in H1993 tumors than in H1299 tumors at 0.5 h (4.74 ± 1.43%/g and 1.00 ± 0.37%/g, respectively; P < 0.05). H1993 tumors were clearly visualized at 0.5 h in SPECT images, whereas H1299 tumors were not observed at any time. The specificity of 99mTc-HYNIC-cMBP for c-Met was demonstrated by a competitive block with an excess of nonradiolabeled peptide. Conclusion: For c-Met-targeted SPECT imaging of NSCLC, we developed 99mTc-HYNIC-cMBP, a tracer that specifically binds to c-Met with favorable pharmacokinetics in vitro and in vivo.

Conversion Therapy for Initially Borderline/Unresectable Metastases in Colon Cancer: What Is the Best Neoadjuvant Chemotherapy?

Resection of metastatic colorectal cancer (mCRC) can dramatically improve overall survival (OS), particularly in patients with isolated colorectal liver metastases (CLMs). In this review, we summarize recent findings and studies addressing chemotherapy ± targeted therapy before and after metastatectomies in patients with CLM. For initially unresectable CLM that could become resectable after response to medical therapy, FOLFIRINOX has the highest response and conversion rates and is safely administered with bevacizumab. In RAS wild-type, left-sided tumors, chemotherapy with Epidermal Growth Factor Receptor-targeted therapy should be strongly considered given high (~ 70%) response rates. In patients who present with resectable CLM, there is no clear indication that neoadjuvant chemotherapy improves OS. While the New EPOC trial showed detrimental progression-free survival in the combination arm containing cetuximab in this setting, methodologic issues with that trial have raised questions about the strength of these data. Through multidisciplinary management in patients with isolated CLM, the best course of action to effect an R0 resection of all known disease-coupling surgery with medical therapy can significantly improve patient outcomes.

Changes in cell junctions induced by inhibition of epidermal growth factor receptor in oral squamous cell carcinoma cells.

The benefits of epidermal growth factor receptor (EGFR) targeting in the treatment of head and neck cancer, have been documented. However, a minority of patients with head and neck cancer are unresponsive to EGFR targeting therapies. The present study evaluated the effects and limitations of an EGFR inhibitor on oral squamous cell carcinoma cells, particularly on cell-cell junctions mediated by epithelial (E)-cadherin. HSC-3 oral squamous cell carcinoma cells were treated with the EGFR inhibitor, AG1478 (0, 0.5, 2, 10 and 50 µM), and the effects of EGFR inhibition in HSC-3 cells were evaluated by wound healing assays, E-cadherin immunostaining and measurement of transepithelial electrical resistance in vitro. It was observed that treatment of oral squamous cell carcinoma cells with AG1478 suppressed cell motility, altered cell morphology and increased the number of cell-cell junctions compared with untreated control cells. Knockdown of EGFR induced a similar phenotype to that observed by the inhibition of EGFR. Furthermore, in oral squamous cell carcinoma cells treated with high-dose EGFR inhibitor (50 µM), the small number of cells that survived formed cell-cell junctions that were positive for E-cadherin expression. In cells treated with low concentrations of EGFR inhibitor (2 µM), recovery of epithelial properties was observed. The retention of E-cadherin expression in cells that survived high-dose EGFR inhibitor treatment may be a survival mechanism of cancer cells.

Targeted Therapy in Head and Neck Cancer: An Update on Current Clinical Developments in Epidermal Growth Factor Receptor-Targeted Therapy and Immunotherapies.

Most patients diagnosed with head and neck squamous cell carcinoma (HNSCC) will present with locally advanced disease, requiring multimodality therapy. Despite this curative approach, a significant subset of these patients will develop locoregional failure and/or distant metastases. Despite significant progress in the treatment and subsequent prognosis of locally advanced HNSCC, the prognosis of those patients with recurrent and/or metastatic (R/M) HNSCC is poor, with short-lived responses to palliative chemotherapy and few therapeutic agents available. The discovery of the integral role of epidermal growth factor receptor overexpression in the pathogenesis of HNSCC, coupled with emerging data on the role of tumor evasion of the immune system, has opened new pathways in the development of novel therapeutic agents for the treatment of R/M HNSCC. As a result, cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, as well as pembrolizumab and nivolumab, monoclonal antibodies targeting programmed cell death 1 (PD-1), are now US Food and Drug Administration approved for the treatment of R/M HNSCC. This review will detail the data supporting the use of these agents, as well as clinical trials evaluating the efficacy of other novel and promising drugs.

Circulating Tumor DNA: Measurement and Clinical Utility.

Circulating tumor DNA (ctDNA) is a component of the "naked" DNA found in blood. It can be isolated from plasma and represents combined genetic material from the primary tumor and metastases. Quantitative and qualitative information about a cancer, including mutations, can be derived using digital polymerase chain reaction and other technologies. This "liquid biopsy" is quicker and more easily repeated than tissue biopsy, yields real-time information about the cancer, and may suggest therapeutic options. All stages of cancer therapy have the ability to benefit from ctDNA, starting with screening for cancer before it is clinically apparent. During treatment of metastatic disease, it is useful to predict response and monitor disease progression. Currently, ctDNA is used in the clinic to select patients who may benefit from epidermal growth factor receptor-targeted therapy in non-small cell lung cancer. In the future, ctDNA technology promises useful applications in every part of clinical oncology care.

Biomarkers predicting resistance to epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer with wild-type KRAS.

EGFR pathway is an important therapeutic target in human tumors, including metastatic colorectal cancer (mCRC). The advent of EGFR-targeted monoclonal antibodies panitumumab and cetuximab has generated promise for the treatment of mCRC and has largely improved patients’ progression-free survival (PFS) and overall survival (OS). However, treatment with anti-EGFR monoclonal antibodies is only effective in a subset of mCRC patients with wild-type KRAS. This indicates that there are other factors affecting the efficacy of anti-EGFR monoclonal antibodies. Existing studies have demonstrated that among colorectal cancer patients with wild-type KRAS, harboring mutations of BRAF, PIK3CA, NRAS, or PTEN-null may demonstrate resistance to anti-EGFR-targeted therapy, and biomarkers detection can provide better-personalized treatment for mCRC patients. How to identify and reverse the secondary resistance to anti-EGFR monoclonal antibody therapy is also another great challenge to improve the anti-EGFR efficacy in wild-type KRAS mCRC patients. Finally, both of the molecular mechanisms of response and acquired resistance would be important for the directions of future research. This review focuses on how to further improve the predictive value of anti-EGFR therapies and how to also try and avoid futile treatment for wild-type KRAS colorectal cancer patients.

Epidermal growth factor receptor-targeted therapy in colorectal cancer

The epidermal growth factor receptor (EGFR) family plays an important role in colorectal cancer (CRC). EGFR participates in the key process of tumorigenesis and invasion, and its expression correlates with the prognosis of CRC. EGFR-targeted therapy has been widely utilized in stage III and IV CRC. The EGFR antibodies, cetuximab and panitumumab, are widely used in treatment of CRC. There are clinical trials and in vivo studies being carried out on the efficacy and mechanism of their action in CRC treatment. In this review, we will describe the EGFR-targeted therapy used in CRC, focusing on the efficacy and mechanisms of the most commonly used EGFR antibodies, cetuximab and panitumumab.

Low incidence of KRAS, BRAF, and PIK3CA mutations in adenocarcinomas of the ampulla of Vater and their prognostic value

Ampullary adenocarcinomas (A-ACs) are rare malignancies with considerable importance because of their high curable resection rate and improved survival rate among periampullary cancers. The RAS-RAF-MAPK pathway is involved in the development of A-ACs and is a potential therapeutic target. However, molecular profiles of A-ACs and their prognostic impact are poorly understood. Peptide nucleic acid-mediated polymerase chain reaction clamping and Mutyper were used to detect KRAS, BRAF, and PIK3CA mutations in 62 paraffinized samples of A-ACs. Of 62 A-ACs, 30.6% had KRAS mutations, but no BRAF mutations and low frequency (1.6%) of PIK3CA mutation were detected. KRAS mutation was correlated with poor tumor differentiation and was a predictor of shorter recurrence-free survival period in overall A-ACs, whereas the prognosis according to the histologic subtypes was not affected by KRAS mutation. Lymph node metastasis was an independent prognostic factor of poor overall survival. Intestinal- and pancreatobiliary-type A-ACs had similar prognosis. Intestinal- and pancreatobiliary-type A-ACs had different prognostic factors; tumor differentiation and lymph node metastasis strongly predicted overall survival and recurrence-free survival in pancreatobiliary-type tumors, respectively, whereas no independent prognostic factors were demonstrated for intestinal-type tumors. Low incidence of KRAS mutations and their strong prognostic value in A-ACs may suggest the potential of survival benefit depending on the epidermal growth factor receptor-targeted therapy. Much lower frequencies of BRAF and PIK3CA mutations may suggest that they do not play a major role in the tumorigenesis of A-ACs. Different therapeutic protocols should be considered for treating pancreatobiliary- and intestinal-type A-ACs.

KRAS, BRAF and gastric cancer

Gastric cancer (GC) remains a major worldwide health problem and survival rates continue to be poor in patients with advanced stage disease despite multimodal treatment combining different chemo(radio)therapy regimens with surgery or best supportive care. Thus, there is an urgent clinical need to identify new potential drug targets in order to improve survival for GC patients. KRAS encodes a small guanosine triphosphatase and point mutations in codons 12 and 13 of KRAS have been detected in many human cancers. BRAF is a member of the RAF family of protein kinases and has a hotspot for mutations in codon 600 (so called V600E mutation). KRAS and BRAF proteins are both components of the MAPK/ ERK pathway. When mutated, KRAS becomes constitutively active resulting in enhanced BRAF activity. KRAS and BRAF mutations in colorectal cancers (CRC) are known predictors of poor response to epidermal growth factor receptor (EGFR) targeting agents. This PubMed and Web of Science based review aimed to analyze and summarize the current literature on mutations in KRAS and BRAF in GC and their relationship to clinicopathological and molecular variables including KRAS amplification. In total, 69 studies were included in this review. The median incidence of a KRAS mutation was 6.5% ranging from 0-29%. The median incidence of KRAS mutations was similar in studies from the East and the West (East: 6%, ranging from 0-20%; West 7.5%, ranging from 0-29%). KRAS amplifications were reported at an incidence of 1-9%. The median BRAF mutation incidence in GC was 0%, ranging from 0% to 12%. Due to the low incidence and often small study size, many of the published studies had insufficient statistical power to detect a potential relationship between KRAS mutation status and clinicopathological variables including patient survival. In summary, the current literature on KRAS and BRAF in GC is still limited and very heterogeneous making any comparisons between different studies difficult. BRAF V600E mutations are very rare in GC. Interestingly, the incidence of KRAS mutations in GC is much lower than that in CRC and there appears to be no difference by ethnicity of the patients. KRAS mutations and KRAS amplifications seem to be mutually exclusive suggesting the need to screen GC patients for both genetic aberrations. So far, all clinical studies in unselected patients with metastatic GC have failed to show a significant benefit for EGFR targeting therapy. However, there has been a recent report indicating that the subgroup of signet ring cell GC, which is known to be resistant to standard cytotoxic chemotherapy, has a higher incidence of KRAS mutations (15%). Thus, EGFR targeted therapy in this particular histological subtype of GC could potentially be a promising treatment option in the future.

Abstract 3585: HER3 and IGF1R are major mediators of both acquired and intrinsic cetuximab resistance in head and neck squamous cell carcinomas

Abstract Head and neck squamous cell carcinoma (HNSCC) is among the leading causes of death worldwide. HNSCC originates from the squamous epithelium of the upper aerodigestive tract, including the lip, oral cavity, pharynx, larynx and paranasal sinuses. The epidermal growth factor receptor (EGFR) has been found to play an essential role in driving the malignancy of HNSCC. The monoclonal antibody targeting EGFR, cetuximab, has been approved for clinical use in HNSCC patients, in combination with either radiation or chemotherapy. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to investigate the molecular mechanisms behind cetuximab resistance in HNSCC, we screened a panel of cell lines for sensitivity to cetuximab. As expected, the cell lines exhibited a varied response to cetuximab. The most sensitive cell line, HN5, was used to establish a number of cetuximab-resistant clones. These resistant clones had lower EGFR levels but remained partially dependent on EGFR, as demonstrated by EGFR gene knockdown and treatment with a mixture of two anti-EGFR antibodies. HER3 and IGF1R are known to be major drivers of resistance to EGFR targeting therapies, and therefore we investigated the role of the two receptors in resistant clones with a mixture of antibodies against EGFR, HER3 and IGF1R. The antibody mixture, which simultaneously blocked EGFR, HER3 and IGF1R signaling, resulted in near total growth inhibition of cetuximab resistant clones. These results were extended to HNSCC cell lines with intrinsic resistance to cetuximab and also in these cell lines the three target mAb mixture led to effective growth inhibition. In conclusion, our results demonstrate that HNSCC cell lines have a heterogeneous response to cetuximab and that HER3 and IGF1R effectively compensate for EGFR inhibition in both the acquired and intrinsic cetuximab resistant setting. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in HNSCC. Citation Format: Ida Kjaer, Trine Lindsted, Camilla Fröhlich, Ivan D. Horak, Michael Kragh, Jesper V. Olsen, Mikkel W. Pedersen. HER3 and IGF1R are major mediators of both acquired and intrinsic cetuximab resistance in head and neck squamous cell carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3585. doi:10.1158/1538-7445.AM2015-3585

Integrin-mediated resistance to epidermal growth factor receptor-targeted therapy: an inflammatory situation.

Targeting the function of epidermal growth factor receptor (EGFR) has failed as an effective clinical option for breast cancer. Understanding the drivers of inherent resistance has been a challenge. One possible mechanism is the acquisition of stem-like properties through the process of epithelial-mesenchymal transition. A recent study by Seguin and colleagues adds to our understanding of this process by demonstrating a functional role for unligated αvβ3 integrin in mediating a stem-like phenotype and facilitating resistance to EGFR-targeted therapy via enhanced downstream coupling to a KRAS:RalB:NF-κB pathway. Importantly, the identified mechanism may reveal a possible strategy for sensitizing breast cancer cells to EGFR-targeted therapies.