Epidermal Growth Factor Receptor In Lung Cancer Research Articles

Investigating the Association between rs712829 Polymorphism of EGFR Gene with Lung Cancer as a Predictive Marker in Iranian Population

Background and Objectives Lung cancer is the leading cause of cancer death globally. The epidermal growth factor receptor (EGFR) plays an important role in cell proliferation and signaling. In this study, we examined the association between EGFR (rs712829) gene polymorphism and lung cancer risk among the Iranian population. Subjects and Methods A total of 100 patients with primary lung cancer and 100 matched healthy controls were recruited into this study. EGFR rs712829 single nucleotide polymorphism (SNP) were genotyped by PCR-RFLP techniques for this association with lung cancer risk. Results A significant association was observed between the GG genotype (P= 0.039, OR= 5.500, CI=95%; 1.710- 11.921) and also G (P= 0.001, OR= 2.967, CI=95%; 1.557- 5.691) allele of rs712829 SNP with lung cancer risk, this was while the TT genotype and T allele of this polymorphism showed a protective role against risk of lung cancer. Conclusion In conclusion, EGFR rs712829 was associated with a risk of lung cancer among Iranians. More studies in other Iranian populations are required to confirm the present findings.

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer EGFR Exon 20 insertion mutations after platinum-based chemotherapy

Background In the single-arm CHRYSALIS trial, advanced non-small cell lung cancer patients harboring epidermal growth factor receptor (EGFR) exon 20 insertion (Exon 20ins) showed durable responses to amivantamab, an EGFR-MET bispecific antibody targeting tumors with EGFR Exon 20ins. This study compared the effectiveness of amivantamab to real-world systemic anti-cancer therapies in Japan. Patients and methods External control patients were selected by applying CHRYSALIS eligibility to Japanese patients from LC-SCRUM-Asia. External control patients were included for every qualifying line of therapy after platinum-based chemotherapy. Propensity score weighting was applied to external control patients to adjust for differences in baseline characteristics. Outcomes were compared between external control patients, and all and Asian-only CHRYSALIS patients using weighted Cox proportional hazards regression models for progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS), and generalized estimating equations with repeated measurements for overall response rate (ORR). Results One hundred fifteen CHRYSALIS and 94 external control patients were identified. Compared to external control patients, amivantamab-treated patients had significantly longer OS (median OS 19.88 vs 14.09 months, HR [95% CI] 0.59 [0.40–0.88]), PFS (median PFS 6.74 vs 4.73 months, HR 0.59 [0.45–0.78]), TTNT (median TTNT 12.16 vs 5.09 months, HR 0.39 [0.29–0.53]), and significantly higher ORR (41.7% vs 14.1%). Analyses of amivantamab-treated Asian patients (n = 61) showed similar clinical benefits. Conclusion In the absence of clinical evidence from randomized clinical trials, this study reflects the benefit of amivantamab after platinum-based chemotherapy for advanced non-small cell lung cancer patients harboring EGFR Exon 20ins, compared to current real-world therapies.

Downregulation of AP1S1 causes the lysosomal degradation of EGFR in non-small cell lung cancer.

Matrix stiffness has been shown to play a critical role in cancer progression by influencing various cellular processes, including epidermal growth factor (EGF) signaling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1), a component of adaptor protein complex-1, in the regulation of EGF receptor (EGFR) intracellular trafficking during cancer cell progression. We found that AP1S1 expression was upregulated under stiff matrix conditions, resulting in the regulation of EGFR trafficking in non-small cell lung adenocarcinoma cells. Knockout of AP1S1 caused the lysosomal degradation of EGFR, leading to suppressed EGF-induced anaplastic lymphoma receptor tyrosine kinase phosphorylation. In addition, the downregulation of AP1S1 increased the sensitivity of H1975 cancer cells, which are resistant to tyrosine kinase inhibitors, to erlotinib. Collectively, our results suggest that AP1S1 could regulate EGFR recycling under stiff matrix conditions, and AP1S1 inhibition could be a novel strategy for treating cancer cells resistant to EGFR-targeted anticancer drugs.

Identification and exploration of quinazoline-1,2,3-triazole inhibitors targeting EGFR in lung cancer

Epidermal growth factor receptor (EGFR) enhances lung cancer development, due to their inability to permeate the cell membrane, secreted growth factors work through specialized signal transduction pathways. The purpose of this study is to find out a novel anticancer agent that inhibits EGFR and reduces the chances of lung cancer. A series of triazole-substituted quinazoline hybrid compounds were designed by Chemdraw software and docked against five different crystallographic EGFR tyrosine kinase domain (TKD). For docking and visualization PyRx, Autodock vina, and Discovery studio visualizer were used. Molecule-14, Molecule-16, Molecule-19, Molecule-20, and Molecule-38 showed significant affinity but Molecule-19 showed excellent binding affinity (−12.4 kcal/mol) with crystallographic EGFR tyrosine kinase. The superimposition of the co-crystalized ligand with the hit compound shows similar conformation at the active site of EGFR (PDB ID: 4HJO) indicating excellent coupling and pharmaceutically active. The hit compound showed a good bioavailability score (0.55) with no sign of carcinogenesis, mutagenesis, or reproductive toxicity properties. MD simulation and MMGBSA represent good stability and binding free energy demonstrating that the hit (Molecule-19) may be used as a lead compound. Molecule-19 also showed good ADME properties, bioavailability scores, and synthetic accessibility with fewer signs of toxicity. It was observed that Molecule-19 may be a novel and potential inhibitor against EGFR with fewer side effects than the reference molecule. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about the amino acid residues involved in binding. Overall, this study led to the identification of potential EGFR inhibitors with favorable pharmacokinetic properties. We believe that the outcome of this study can help to develop more potent drug-like molecules to tackle human lung cancer.

Coupled folding-upon-binding of human tumor suppressor MIG6 to lung cancer EGFR kinase domain and molecular trimming/stapling of MIG6-derived β-hairpins to target the coupling event.

Human epidermal growth factor receptor (EGFR) is involved in strong association with malignant proliferation, which has been shown to play a central role in the development and progression of non-small cell lung cancer and other solid tumors. The tumor-suppressor protein MIG6 is a negative regulator of EGFR kinase activity by binding at the activation interface of asymmetric dimer of EGFR kinase domain to disrupt EGFR dimerization and then inactivate the kinase. The protein adopts two discrete fragments 1 and 2 to directly interact with EGFR. It is revealed that the MIG6 fragment 2 is intrinsically disordered in free unbound state, but would fold into a well-structured β-hairpin when binding to EGFR, thus characterized by a so-called coupled folding-upon-binding process, which can be regarded as a compromise between favorable direct readout and unfavorable indirect readout. Here, a 23-mer F2P peptide was derived from MIG6 fragment 2, trimmed into a 17-mer tF2P peptide that contains the binding hotspot region of the fragment 2, and then constrained with an ordered hairpin conformation in free unbound state by disulfide stapling, finally resulting in a rationally stapled/trimmed stF2P peptide that largely minimizes the unfavorable indirect readout effect upon its binding to EGFR kinase domain, with affinity improved considerably upon the trimming and stapling/trimming. These rationally designed β-hairpin peptides may be further exploited as potent anti-lung cancer agents to target the activation event of EGFR dimerization.

EP08.02-003 Aumolertinib Plus Chemotherapy as 1st Line Treatment in Advanced Lung Cancer EGFR Mutation andctDNA Cleared Analysis

Aumolertinib is a novel third-generation epidermal growth factor receptor (EGFR)-targeted oral tyrosine kinase inhibitor (TKIs). The positive phase III trial (AENEAS) reported objective response rate (ORR) was 73.8% and medium progression-free survival (mPFS) was 19.3 months which aumolertinib as 1st line treatment of patients with EGFR mutation Non-Small Cell Lung Cancer (NSCLC). An improved efficacy of the combination of first-generation EGFR-TKI and carboplatin plus pemetrexed was confirmed in NEJ009 study.

What do we know about the molecular and biological features of EGFR in glioblastomas and non-small cell lung cancer?

The EGFR mutation is one of the most common mutations in malignant neoplasms. The epidermal growth factor receptor (EGFR) is a growth factor receptor that induces cell differentiation and proliferation when activated by binding one of its ligands. The receptor is located on the cell surface, where ligand binding activates a tyrosine kinase in the intracellular region of the receptor. The tyrosine kinase phosphorylates a number of intracellular substrates and further activates pathways leading to cell growth, DNA synthesis and oncogene expression. Gene amplification is a process characterized by an increase in the copy number of a restricted region in the chromosome shoulder, which is associated with overexpression of the corresponding amplified gene. Amplification of the EGFR gene is detected in about 40% of glioblastoma cases. It should be noted that EGFR gene amplification is accompanied by the acquisition of many mutations, which include intragenic deletions and point mutations. The most common EGFR mutation in glioblastomas of the brain is a deletion in exon 2-7 (EGFRvIII) frame, which occurs in 50% of all cases of EGFR-amplified glioblastoma. Despite great advances in molecular biology and targeted therapies, patients with non-small cell lung cancer (NSCLC) and glioblastoma still lead in mortality. Most of them have “classical” EGFR mutations (deletions in exon 19 and 21), but 15-20% of patients have rare mutations, which most often include point mutations, deletions and insertions in exon 18 and 25. Thus, rare EGFR mutations are a promising diagnostic and therapeutic target in cancer. This review summarizes data on the role of EGFR in the carcinogenesis of NMPL and glioblastoma. The literature search was performed using the Pubmed database.

An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.

Natural alkaloids targeting EGFR in non-small cell lung cancer: Molecular docking and ADMET predictions

The phytochemicals contribute to the processes of protection and interaction by acting as antioxidants, anti-mutagens, anticarcinogens, and antimicrobial agents. Among the diverse families of phytoconstituents, alkaloids play an essential role in medicine. These are low-molecular-mass compounds containing nitrogen and are generally alkaline. In this study, in silico molecular docking was performed using AutoDock Vina for thirty-one alkaloids against epidermal growth factor receptor (EGFR). Erlotinib was used as a reference ligand for this study. Erlotinib has been linked to various serious side effects over the past decade, including folliculitis, diarrhoea, paronychia, fatigue, conjunctivitis, ectopion, and epiphora of the lower eyelids. This study found sanguinarine (−10.7 kcal mol−1) to be the most potent inhibitor of EGFR as compared to erlotinib (−7.5 kcal mol−1). Other alkaloids namely, isocolumbin (−9.3 kcal mol−1), lunamarine (−9.1 kcal mol−1), ajmaline (−8.6 kcal mol−1), magnoflorine (−8.6 kcal mol−1) and jatrorrhizine (−8.5 kcal mol−1) also showed potent inhibition against EGFR, but the stability of these molecules with EGFR was less than sanguinarine and more than erlotinib. These were stable and ideal pharmaceutical alkaloids because of their significant interactions, minimal Gibbs free energy, safety, effectiveness and selectivity. Amongst the 31 alkaloids subjected to ADMET prediction, 29 alkaloids followed Lipinski's rule of five. These 29 alkaloids were predicted to have high bioavailability, high lead-likeness score, low toxicity and were easier to synthesize. Compared to erlotinib, other molecules showed less or no inhibition of EGFR. The six named compounds listed above may be potent inhibitors for EGFR mutated cancers, as for example non-small cell lung cancer, colorectal cancer, and pancreatic cancer.

Evaluation of Amide Proton Transfer-Weighted Imaging for Lung Cancer Subtype and Epidermal Growth Factor Receptor: A Comparative Study With Diffusion and Metabolic Parameters.

Lung cancer is one of the most devastating diseases worldwide, and it is meaningful to assess the subtype and epidermal growth factor receptor (EGFR) status in lung cancer noninvasively by imaging methods. To differentiate noninvasively small cell lung cancer (SCLC) from nonsmall cell lung cancer (NSCLC), and EGFR mutation-type from wild-type NSCLC by comparing amide proton transfer-weighted imaging (APTWI), diffusion-weighted imaging (DWI), and 2-[18 F]-fluoro-2-deoxy-d-glucose positron emission tomography (18 F-FDG PET). Prospective. A total of 99 patients with lung cancer. APTWI and DWI at 18 F-FDG PET/MRI 3.0 T. The apparent diffusion coefficient (ADC), magnetization transfer ratio asymmetry (MTRasym [3.5ppm]), maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated and compared. Individual sample t-test, Mann-Whitney U test, Logistic regression, and P < 0.05 were considered statistically significant. In NSCLC, MTRasym (3.5ppm), MTV, and TLG were significantly lower and ADC was significantly higher than in SCLC; MTRasym (3.5ppm) was significantly higher and SUVmax , MTV, and TLG were significantly lower in EGFR mutation-type NSCLC than in EGFR wild-type NSCLC. In the identification of SCLC and NSCLC, MTRasym (3.5ppm), ADC, and MTV were independent predictors, the AUCs of the combination of independent predictors, MTV, TLG, MTRasym (3.5ppm), and ADC were 0.942, 0.875, 0.843, 0.814, and 0.687, respectively. In the identification of EGFR mutation-type and wild-type NSCLC, MTRasym (3.5ppm) and MTV were independent predictors, the AUCs of the combination of independent predictors, TLG, MTV, MTRasym (3.5ppm), and SUVmax were 0.919, 0.834, 0.813, 0.795, and 0.771, respectively. In the noninvasive assessment of lung cancer subtype and EGFR status, APTWI has similar utility to diffusion and metabolic parameters. 2 TECHNICAL EFFICACY STAGE: 2.

Chemical Genetics Screen Identifies COPB2 Tool Compounds That Alters ER Stress Response and Induces RTK Dysregulation in Lung Cancer Cells

Activating mutations in the epidermal growth factor receptor (EGFR) are common driver mutations in non-small cell lung cancer (NSCLC). First, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are effective at inhibiting mutant EGFR NSCLC, however, acquired resistance is a major issue, leading to disease relapse. Here, we characterize a small molecule, EMI66, an analog of a small molecule which we previously identified to inhibit mutant EGFR signalling via a novel mechanism of action. We show that EMI66 attenuates receptor tyrosine kinase (RTK) expression and signalling and alters the electrophoretic mobility of Coatomer Protein Complex Beta 2 (COPB2) protein in mutant EGFR NSCLC cells. Moreover, we demonstrate that EMI66 can alter the subcellular localization of EGFR and COPB2 within the early secretory pathway. Furthermore, we find that COPB2 knockdown reduces the growth of mutant EGFR lung cancer cells, alters the post-translational processing of RTKs, and alters the endoplasmic reticulum (ER) stress response pathway. Lastly, we show that EMI66 treatment also alters the ER stress response pathway and inhibits the growth of mutant EGFR lung cancer cells and organoids. Our results demonstrate that targeting of COPB2 with EMI66 presents a viable approach to attenuate mutant EGFR signalling and growth in NSCLC.

Radiomic Feature-Based Nomogram: A Novel Technique to Predict EGFR-Activating Mutations for EGFR Tyrosin Kinase Inhibitor Therapy.

ObjectivesTo develop and validate a radiomic feature-based nomogram for preoperative discriminating the epidermal growth factor receptor (EGFR) activating mutation from wild-type EGFR in non-small cell lung cancer (NSCLC) patients.MaterialA group of 301 NSCLC patients were retrospectively reviewed. The EGFR mutation status was determined by ARMS PCR analysis. All patients underwent nonenhanced CT before surgery. Radiomic features were extracted (GE healthcare). The maximum relevance minimum redundancy (mRMR) and LASSO, were used to select features. We incorporated the independent clinical features into the radiomic feature model and formed a joint model (i.e., the radiomic feature-based nomogram). The performance of the joint model was compared with that of the other two models.ResultsIn total, 396 radiomic features were extracted. A radiomic signature model comprising 9 selected features was established for discriminating patients with EGFR-activating mutations from wild-type EGFR. The radiomic score (Radscore) in the two groups was significantly different between patients with wild-type EGFR and EGFR-activating mutations (training cohort: P<0.0001; validation cohort: P=0.0061). Five clinical features were retained and contributed as the clinical feature model. Compared to the radiomic feature model alone, the nomogram incorporating the clinical features and Radscore exhibited improved sensitivity and discrimination for predicting EGFR-activating mutations (sensitivity: training cohort: 0.84, validation cohort: 0.76; AUC: training cohort: 0.81, validation cohort: 0.75). Decision curve analysis demonstrated that the nomogram was clinically useful and surpassed traditional clinical and radiomic features.ConclusionsThe joint model showed favorable performance in the individualized, noninvasive prediction of EGFR-activating mutations in NSCLC patients.

Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer.

As one of the major types of lung cancer, non-small cell lung cancer (NSCLC) accounts for the majority of cancer-related deaths worldwide. Treatments for NSCLC includes surgery, chemotherapy, and targeted therapy. Among the targeted therapies, resistance to inhibitors of the epidermal growth factor receptor (EGFR) is common and remains a problem to be solved. MET (hepatocyte growth factor receptor) amplification is one of the major causes of EGFR-tyrosine kinase inhibitor (TKI) resistance. Therefore, there exists a need to find new and more efficacious therapies. Deoxypodophyllotoxin (DPT) extracted from Anthriscus sylvestris roots exhibits various pharmacological activities including anti-inflammation and anti-cancer effects. In this study we sought to determine the anti-cancer effects of DPT on HCC827GR cells, which are resistant to gefitinib (EGFR-TKI) due to regulation of EGFR and MET and their related signaling pathways. To identify the direct binding of DPT to EGFR and MET, we performed pull-down, ATP-binding, and kinase assays. DPT exhibited competitive binding with ATP against the network kinases EGFR and MET and reduced their activities. Also, DPT suppressed the expression of p-EGFR and p-MET as well as their downstreat proteins p-ErbB3, p-AKT, and p-ERK. The treatment of HCC827GR cells with DPT induced high ROS generation that led to endoplasmic-reticulum stress. Accordingly, loss of mitochondrial membrane potential and apoptosis by multi-caspase activation were observed. In conclusion, these results demonstrate the apoptotic effects of DPT on HCC827GR cells and signify the potential of DPT to serve as an adjuvant anti-cancer drug by simultaneously inhibiting EGFR and MET.

Targeting USP13-mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non-small cell lung cancer.

In non‐small cell lung cancer (NSCLC), activating mutations in the epidermal growth factor receptor (EGFR) induce sensitivity to EGFR tyrosine kinase inhibitors. Despite impressive clinical responses, patients ultimately relapse as a reservoir of drug‐tolerant cells persist, which ultimately leads to acquired resistance mechanisms. We performed an unbiased high‐throughput siRNA screen to identify proteins that abrogate the response of EGFR‐mutant NSCLC to EGFR‐targeted therapy. The deubiquitinase USP13 was a top hit resulting from this screen. Targeting USP13 increases the sensitivity to EGFR inhibition with small molecules in vitro and in vivo. USP13 selectively stabilizes mutant EGFR in a peptidase‐independent manner by counteracting the action of members of the Cbl family of E3 ubiquitin ligases. We conclude that USP13 is a strong mutant EGFR‐specific cotarget that could improve the treatment efficacy of EGFR‐targeted therapies.

Current management and future prospect of HER-2 mutant non-small cell lung cancer

Since Erb-B2 receptor tyrosine kinase 2 (HER-2) was regarded as oncogenic driver gene for malignancies, HER-2 targeted therapy has benefited many patients with breast cancer and gastric cancer. However, as a member of the epidermal growth factor receptor (EGFR) family, HER-2 has failed to respond well to both traditional anti-HER-2 and anti-EGFR targeted agents when compared to EGFR in non-small cell lung cancer (NSCLC). It is reported that unlike gene copy number variation in breast cancer, HER-2 intragenic kinase domain mutations (the exon 20 in-frame insertions are dominant, and missense mutations in kinase domain are also observed) in NSCLC might account for the poor response to traditional HER-2 or EGFR tyrosine kinase inhibitors (TKIs). In this review, we summarize the pathogenesis, molecular variations, clinical features and current therapeutic strategies for HER-2 mutated NSCLC to discuss the challenges and perspectives for this population.

Abstract 1675: Enhanced antitumor effect of dual EGFR and VEGFR2 inhibition in EGFR-mutated non-small cell lung cancer (NSCLC) patient-derived tumor xenograft (PDX) models

Abstract Background: NSCLC accounts for nearly 85% of all lung cancers. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for EGFR mutated NSCLCs, but these drugs often stop working after EGFR acquires additional mutations. Preclinical and clinical data suggest a stronger antitumor effect with dual blockade of the EGFR and vascular endothelial growth factor (VEGF) pathways in EGFR-mutated NSCLC. RELAY, a randomized, double-blind, phase 3 trial, demonstrated superior progression-free survival (PFS) with ramucirumab (RAM) + erlotinib compared with placebo + erlotinib in patients with untreated EGFR-mutated advanced NSCLC. Additionally, RAM was tested in a Phase 1 study with the third-generation irreversible EGFR TKI osimertinib (OSI); AstraZeneca) in NSCLC patients with advanced T790M-positive EGFR mutant tumors after progression on first-line EGFR TKI therapy. OSI can be used with L858R, exon 19 del and T790M EGFR mutant tumors. We investigated the combined use of OSI+RAM in EGFR mutated NSCLC PDX mouse models. Materials and Methods: The antimurine VEGFR2 antibody DC101 (40 mg/kg, BIW) and the EGFR TKI OSI (10 mg/kg, QD) were used in this study. Twenty-seven PDX NSCLC mouse models carrying EGFR activating and/or T790M resistance mutations, commonly detected in patients with advanced NSCLC, were evaluated at 3 independent sites. Mice were divided into 4 treatment arms: vehicle (PBS), DC101, OSI and combination (DC101+OSI). Each study arm included two transplanted mice per model. Sensitivity to DC101 and OSI monotherapies, enhancement of anti-tumor activity with the combination therapy and durability of the response were evaluated. Desirability score, a weighted composite score of six features of tumor growth curves including best median % response, number of days in best response category, time to doubling, re-growth rate (last 5 observations) relative to vehicle growth rate, last observed tumor volume and last observed day, was calculated for each treatment arm. Analysis of variance was used to compare summary scores per animal across treatments. Results: OSI alone and OSI+DC101 combination therapy had stronger antitumor effects than DC101 monotherapy in significantly more models 11 vs 1 and 12 vs 0, respectively. A small but consistent shift in favor of OSI+DC101 vs OSI was observed across most of the models. Paired t-test analyses showed a moderate but significant benefit with combination OSI+DC101 vs OSI. Overall desirability score was statistically improved with OSI+DC101 compared to either single agent. Conclusions: Dual inhibition of EGFR and VEGFR2 with OSI+DC101 had a stronger antitumor effect than those of the respective monotherapies in EGFR mutated NSCLCs in vivo. Future studies will investigate the molecular mechanisms underlying the enhanced antitumor effect of OSI+DC101 combination therapy. Citation Format: Sudhakar Chintharlapalli, Anthony Fischl, Chun Ping Yu, Philip Iversen. Enhanced antitumor effect of dual EGFR and VEGFR2 inhibition in EGFR-mutated non-small cell lung cancer (NSCLC) patient-derived tumor xenograft (PDX) models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1675.

Association of CD8 T cell apoptosis and EGFR mutation in non-small lung cancer patients.

BackgroundThe abundance of tumor infiltrating CD8 T cells is an important parameter for antitumor effect of PD‐1/PD‐L1 immune checkpoint inhibitors, which is less in epidermal growth factor receptor (EGFR) mutation than wild‐type non‐small cell lung cancer (NSCLC). The mechanism still requires further study.MethodsIn total 190 surgical lung adenocarcinoma samples were included. EGFR mutation was detected using amplification‐refractory mutation system. CD8 T cells and apoptosis were assessed by immunohistochemistry and immunofluorescence staining in tumor samples. Exosomes extracted from lung cancer cell lines with and without EGFR mutation were used to test the function of promoting apoptosis in vitro.ResultsThe ratio of CD8 tumor infiltration lymphocytes was significantly lower in EGFR‐mutant than in wild‐type patients (P = 0.026). A higher ratio of apoptosis was also prone to occur in EGFR‐mutant patients (P = 0.035). The distribution of apoptosis was not statistically associated with the ratio of CD8 TILs. An in vitro experiment indicated that exosomes secreted by EGFR‐mutant non‐small cell lung cancer cell lines PC9 and HCC827 were more capable of promoting CD8 T cell apoptosis than EGFR wild‐type cell lines H1299 and SK‐MES‐1 (P = 0.007 and P = 0.010, respectively).ConclusionsNon‐small cell lung cancer EGFR mutation could promote CD8 T cell apoptosis more than wild‐type. Inhibiting CD8 + TILs apoptosis may strengthen immunotherapy effects in EGFR‐mutant NSCLC patients.

The Association between Epidermal Growth Factor Receptor (EGFR) Gene Polymorphisms and Lung Cancer Risk

Lung cancer is the leading cause of cancer death globally. The epidermal growth factor receptor (EGFR) plays an important role in cell proliferation and signaling. In this study, we examined the association between EGFR gene polymorphisms and lung cancer risk among the Jordanian population. A total of 129 patients with primary lung cancer and 129 matched healthy controls were recruited into this study. EGFR rs712829, rs712830, rs2072454, and rs11543848 single nucleotide polymorphisms (SNPs) were genotyped to test for their association with lung cancer risk. A significant association was observed between the rs712829 SNP and lung cancer risk (p &lt; 0.05) where the GG + GT genotypes were higher in lung cancer patients when compared to controls. In addition, no association was detected between rs712830, rs2072454, and rs11543848 SNPs and lung cancer risk. When patients were stratified according to the lung cancer type, a significant association was detected between both rs712829 and rs2072454 and adenocarcinoma lung cancer (p &lt; 0.05). Haplotype analysis of all four SNPs showed a significant association between the TCCG haplotype and both lung cancer and the adenocarcinoma subtype (p &lt; 0.001). In conclusion, EGFR rs712829, rs2072454 SNPs, and TCCG haplotypes are associated with a risk of lung cancer among Jordanians. Since genetic associations are affected by the genetic background of populations, more studies in other Arab populations are required to confirm the present findings.Support or Funding InformationThe study was supported by funding provided by the Ministry of Higher Education—Scientific Research Fund (SRF) grant number JUST‐1‐2016. Genotypes/Allele Pattern Patients Controls p‐Value For rs712829 GG 12 (28%) 29 (22%) 0.020 TT 4 (9%) 35 (27%) GT 27 (63%) 65 (50%) For rs712830 CC 41 (95%) 121 (94%) 0.670 CA 2 (5%) 8 (6%) For rs2072454 CC 6 (14%) 15 (12%) 0.027 TT 26 (60%) 57 (44%) CT 11 (26%) 57 (44%) For rs11543848 AA 8 (19%) 26 (20%) 0.073 GG 2 (5%) 18 (14%) GA 33 (77%) 85 (66%) Note: Rs29: rs712829, Rs30: rs712830, Rs54: rs2072454 and Rs48: rs11543848. Haplotype Rs29 Rs30 Rs54 Rs48 Frequency Odd Ratio (95% CI) p‐Value 1 T C T A 0.2118 1.00 — 2 G C T A 0.1748 1.00 (0.31–3.24) 1 3 G C T G 0.1552 0.93 (0.34–2.55) 0.9 4 T C T G 0.1228 1.38 (0.32–5.96) 0.66 5 G C C G 0.0953 1.08 (0.31–3.67) 0.91 6 T C C A 0.0794 1.46 (0.33–6.43) 0.62 7 G C C A 0.0681 0.69 (0.15–3.15) 0.63 8 T C C G 0.0629 168,507 (168,498–168,517) &lt;0.001 9 G A T G 0.0156 0.71 (0.08–6.39) 0.76 Note: Rs29: rs712829, Rs30: rs712830, Rs54: rs2072454 and Rs48: rs11543848.

Cyclooxygenase-2 contributes to mutant epidermal growth factor receptor lung tumorigenesis by promoting an immunosuppressive environment

Targeted therapies reduce growth of mutant epidermal growth factor receptor (EGFR) non-small cell lung cancers, but most patients develop drug resistance. This has led to efforts to develop additional therapies. We found abundant activation of the cyclooxygenase-2 (COX-2) axis in a mouse model of mutant EGFR lung cancer. Inhibiting COX-2 in the mice significantly reduced lung tumor growth, and dual targeting of COX-2 and EGFR had more pronounced effects. Collectively, our data and published data have led us to hypothesize that COX-2 contributes to mutant EGFR lung tumorigenesis, in part, by promoting an immunosuppressive environment that facilitates tumor progression.

P2.01-77 PET CT Radiogenomic Depiction with EGFR and ALK Molecular Alterations in Lung Cancer Among Indian Population

Non small cell lung cancer (NSCLC) represents an area of paramount importance wherein patients undergo testing for targetable genetic alterations. Association between the imaging and molecular phenotypes is vital highlighting the growing importance and unmet need of classifications based on radio genomic characterization. This study was conducted to evaluate the correlations between the radiologic and molecular phenotypes in patients with NSCLC. 211 patients with lung cancers during the study period of one year from October 2017 till November 2018 in our institution and undergoing both radiologic (PET-CT) and molecular investigations [Epidermal Growth Factor Receptor (EGFR), Anaplastic lymphoma kinase (ALK)] were included in the study. Both quantitative and qualitative CT findings were evaluated and correlated with the molecular findings. Quantitative data included SUV max obtained from PET component of CT and maximum diameter of lesion according to the RECIST criteria. Qualitative data recorded included location, pleural tail, pleural effusion, pericardial effusion, opacity, margins, calcifications, obstructive changes, pleural nodules, lung nodules, invasion, air bronchogram, emphysema, pulmonary fibrosis, mediastinal lymph nodes and distant metastasis. Statistical analysis was performed to evaluate the association of the qualitative features with the molecular expression. Receiver operating characteristic curves (ROC) were drawn and the corresponding area under curve (AUC) was calculated. P-values <0.05 were considered significant. Overall, EGFR mutation positivity and ALK rearrangement was observed in 114 and 37 patients, respectively whereas 60 patients had neither of these. SUV max was comparable between the groups with EGFR mutation (11.3 ± 3.9) and ALK rearrangement (12.3 ± 4.0). Correlations were observed between EGFR mutation and ALK rearrangement and location (p-value <0.0001), pleural tail (p-value <0.0001), pleural effusion (p-value <0.0001), obstructive changes (p-value <0.025), pleural nodule (p-value <0.002), lung nodules (p-value <0.002), air bronchogram (p-value <0.002), emphysema (p-value <0.002), mediastinal nodes (p-value <0.002) and distant metastasis (p-value <0.002). EGFR mutation also correlated with invasion (p-value 0.022). In ROC curves, for EGFR mutation and ALK rearrangement prediction based on mediastinal lymph nodes, the AUC was 0.661 and 0.588, respectively. The correlation between CT findings and molecular findings highlights the importance of newer radio genomic based characterization for patients with NSCLC for better diagnostic and prognostic approaches.