scholarly journals An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Polona Safaric Tepes ◽  
Debjani Pal ◽  
Trine Lindsted ◽  
Ingrid Ibarra ◽  
Amaia Lujambio ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Chemotherapeutic Agents ◽  
Epigenetic Switch ◽  
Lung Cancers ◽  
Oncogenic Mutations ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
A Cell ◽  
Egfr Tki ◽  
Resistant Cells

Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. This is mainly due to the resistance that patients develop against chemotherapeutic agents over the course of treatment. In the context of non-small cell lung cancers (NSCLC) harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a sub-population of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines, and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR-oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.

scholarly journals An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression

2021 ◽  
Author(s):  
Raffaella Sordella ◽  
Debjani Pal ◽  
Polona Safaric Tepes ◽  
Trine Lindsted ◽  
Ingrid Ibarra ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Epigenetic Switch ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Oncogenic Mutations ◽  
A Cell ◽  
Egfr Tki ◽  
Related Mortality ◽  
Resistant Cells

Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. Many lung cancer patients will develop resistance to chemotherapeutics. In the context of non-small cell lung cancers harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive Erlotinib resistance in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a sub-population of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines, and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.

scholarly journals Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1590
Author(s):  
Kenichi Suda ◽  
Tetsuya Mitsudomi
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Drug Tolerance ◽  
Lung Cancers ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutated

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.

scholarly journals A Case Report of Primary Resistance to EGFR TKI in Lung Adenocarcinoma Due to Coexisting MET Exon 14 Skipping Mutation with Excellent Response to Combination of Gefitinib and Capmatinib

2021 ◽  
Author(s):  
Nirmal Vivek Raut ◽  
Siddharth Srivastava ◽  
Guarav Dilip Gangwani ◽  
Heena Sajid Ali
Keyword(s):  
Kinase Inhibitors ◽  
Single Gene ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Primary Resistance ◽  
Gene Testing ◽  
Comprehensive Genomic Profiling ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Next Generation Sequencing Ngs ◽  
Egfr Tki

AbstractTreatment of nonsmall cell lung cancer (NSCLC) carrying an epidermal growth factor receptor (EGFR) mutation depends on EGFR tyrosine kinase inhibitors (TKIs). However, all patients treated with EGFR TKI eventually develop progressive disease. Approximately, 20% of patients do not respond to EGFR TKIs, which is defined as primary resistance. The prognosis of these patients is similar to NSCLC with nondriver mutations. We report a case of a patient with EGFR exon 21 mutation who rapidly progressed in 15 days on Gefitinib. Next-generation sequencing (NGS) showed a MET exon 14 skip mutation coexisting with EGFR exon 21 mutation, causing primary resistance to EGFR TKI. Based on NGS reports, a treatment combining Gefitinib and Capmatinib, a MET inhibitor, induced a rapid response in the patient, which was sustained at the end of 8 months. This clearly emphasizes the need for comprehensive genomic profiling using NGS over single gene testing.

scholarly journals EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging therapy

Oncotarget ◽  
2015 ◽  
Vol 6 (19) ◽  
pp. 17491-17500 ◽  
Author(s):  
Yun-Tian Li ◽  
Xiao-Jun Qian ◽  
Yan Yu ◽  
Zhen-Hua Li ◽  
Rui-Yan Wu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Caspase 8 ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

scholarly journals Non-Small-Cell Lung Cancer-Sensitive Detection of the p.Thr790Met EGFR Alteration by Preamplification before PNA-Mediated PCR Clamping and Pyrosequencing

Diagnostics ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 527
Author(s):  
Amandine Billaud ◽  
Veronique Verriele ◽  
Jonathan Dauvé ◽  
Louise-Marie Chevalier ◽  
Alain Morel
Keyword(s):  
First Generation ◽  
Kinase Inhibitors ◽  
Resistance Mutation ◽  
Small Cell ◽  
Therapeutic Management ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Ffpe Samples ◽  
Egfr Tyrosine Kinase Inhibitors

Targeted therapies and, more precisely, EGFR tyrosine kinase inhibitors (TKIs) have been a major improvement in the therapeutic management of EGFR-mutated non-small-cell lung cancers (NSCLCs). Earlier administration of these TKIs throughout tumor progression is imperative to improve patient outcomes. Consequently, studies have focused on refining the characterization of biomarkers, especially concerning the resistance mutation p.Thr790Met of EGFR. Herein, we developed peptide nucleic acid (PNA)-mediated PCR clamping followed by pyrosequencing, favoring enrichment of the mutated fraction. A preamplification step was first added to increase the amplifiable DNA fraction. Throughout the application of our method on DNA extracted from FFPE samples of 46 patients with NSCLC who had relapsed under first-generation EGFR TKI, we evaluated a sensitivity of 93.3% and a specificity of 100%. All 19 patients who were positive for the p.Thr790Met mutation with NGS were also found to be positive with our protocol. The only discordant case was a sample with no mutation detected with NGS, but which was positive with PNA. This protocol allows for the detection of the p.Thr790Met mutation with a sensitivity of 0.5% which will permit earlier detection and an improvement of therapeutic management.

Exon-16-skipping ERBB2 (ERBB2ΔEx16) as a novel resistance mechanism against EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9528-9528
Author(s):  
Xin Zhao ◽  
Linling Jin ◽  
Man Yu ◽  
Qiuxiang Ou ◽  
Hua Bao ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Small Cell ◽  
Large Fragment ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr Mutated ◽  
Egfr Tki ◽  
Egfr T790m ◽  
Erbb2 Amplification

9528 Background: In addition to ERBB2 amplification/protein overexpression, activating ERBB2 alterations have been increasingly discovered in diverse human cancers with varying incidence. ERBB2ΔEx16 is an alternatively spliced isoform of ERBB2, lacking the entire exon 16 which encodes a small extracellular domain. ERBB2ΔEx16 was recently reported to lead to oncogenic activation of ERBB2 and osimertinib resistance in EGFR T790M+ non-small cell lung cancer (NSCLC). Methods: A total of 38,680 Chinese cancer patients whose tumor specimen or circulating cell-free DNA underwent genomic profiling by targeted next-generation sequencing of cancer-related genes were retrospectively reviewed. Clinicopathological features and treatment history of ERBB2ΔEx16+ patients were evaluated. RNA sequencing was performed to validate the presence of exon-16-skipping ERBB2 at the transcriptional level. Results: A total of eighteen ERBB2ΔEx16+ patients (11 NSCLC, 2 colorectal cancer, 2 gastric cancer, and 3 others) were identified (0.047%, 18/38,680). ERBB2 exon 16 skipping may result from large fragment deletion spanning the whole or partial region of exon 16 (72.2%, 13/18), base substitution at the splice acceptor site (16.7%, 3/18) and deletion of the splice donor site (11.1%, 2/18). ERBB2 exon 16 skipping, including large fragment deletion and splice site deletion, was validated at the RNA level by RNA sequencing in 3 patients with available samples. Co-occurrence of ERBB2 amplification and ERBB2 mutations were found in 83.3% (15/18) and 50% (9/18) of cases, respectively. Concurrent copy number variations were prevalent in CDK12 (55.6%, 10/18), CDKN2B (44.4%, 8/18), NKX2.1 (38.9%, 7/18) and PTPRD (33.3%, 6/18). Among the 11 cases of ERBB2ΔEx16+ NSCLC, 9 had coexisting activating EGFR mutations (exon 19 deletions, exon 21 L858R) and received prior treatment with EGFR tyrosine kinase inhibitors (TKIs), with 2 harboring acquired EGFR T790M mutation and 1 EGFR copy number gain. Further analysis of the matched pretreatment samples in 3 EGFR-mutated NSCLC patients confirmed that ERBB2ΔEx16 was acquired during EGFR TKI therapy. In the 7 cases of other cancers, 4 to 31 non- ERBB2 mutations were identified in each sample, with TP53 being the most frequently mutated gene. Conclusions: Our data suggest that ERBB2ΔEx16 may be a general mechanism of EGFR TKI resistance in a subset of EGFR-mutated NSCLC patients, in addition to being an oncogenic driver as reported in some solid malignancies including colorectal, gastric and ovarian cancers.

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