Amplification of EGFR Wild-Type Alleles in Non–Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors

Nukaga, Shigenari; Yasuda, Hiroyuki; Tsuchihara, Katsuya; Hamamoto, Junko; Masuzawa, Keita; Kawada, Ichiro; Naoki, Katsuhiko; Matsumoto, Shingo; Mimaki, Sachiyo; Ikemura, Shinnosuke; Goto, Kōichi; Betsuyaku, Tomoko; Soejima, Kenzo

doi:10.1158/0008-5472.can-16-2359

Cited by 136 publications

(120 citation statements)

References 49 publications

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“…In contrast, expression of E-cadherin and vimentin was similar in PC9 and PC9-ER cells Figure 2D), with PC9-ER cells having a lower invasion potential than their parental counterparts (0.52 relative invading fraction in PC9-ER compared to PC9 parental cells; Figure 2E). Similar results were previously reported by others: PC9 cells with acquired resistance to osimertinib maintained epithelial phenotype, while H1975 osimertinib-resistant cells developed mesenchymal features [28][29][30]. Overall, two out of three EGFR TKI-resistant models we developed (H1975-OR and SH416-ER) underwent EMT.…”

Section: Egfr Tki Resistance Is Associated With Emtsupporting

confidence: 90%

“…This is an important discovery since it points towards a potential opportunity to utilize vitamin D-based combination therapies in the setting of progressive disease. As a mechanism of resistance to EGFR TKIs, EMT is commonly observed in pre-clinical models [7,[27][28][29][30]44]. In the clinic, EMT is believed to cause EGFR TKI failure in a small proportion (~6%) of EGFR-mutant LUAD patients [4].…”

Section: 25(oh)2d3 Is Known To Induce Transcription Of Multiple Celmentioning

confidence: 99%

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Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

Shaurova

Battaglia

et al. 2020

Cancers

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EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with EGFR-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. We hypothesized that vitamin D metabolites could be used with EGFR TKIs to prevent therapeutic failure. To test this idea, we investigated the link between serum 25-hydroxyvitamin D3 (25(OH)D3) and progression-free survival (PFS) in patients with EGFR-mutant LUAD that received EGFR TKIs (erlotinib n = 20 and afatinib n = 1). Patients who were 25(OH)D3-sufficient experienced significantly longer benefit from EGFR TKI therapy (mean 14.5 months) than those with 25(OH)D3 insufficiency (mean 10.6 months, p = 0.026). In contrast, 25(OH)D3 had no prognostic value in patients with KRAS-mutant LUAD that received cytotoxic chemotherapy. To gain mechanistic insights, we tested 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity in vitro. 1,25(OH)2D3 promoted epithelial differentiation and restored EGFR TKI sensitivity in models of EGFR TKI resistance that were associated with epithelial-mesenchymal transition (EMT). 1,25(OH)2D3 was ineffective in a non-EMT model of resistance. We conclude that vitamin D sufficiency portends increased PFS among EGFR-mutant LUAD patients that receive EGFR TKIs, and that vitamin D signaling maintains drug efficacy in this specific patient subset by opposing EMT.

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Section: Egfr Tki Resistance Is Associated With Emtsupporting

confidence: 90%

Section: 25(oh)2d3 Is Known To Induce Transcription Of Multiple Celmentioning

confidence: 99%

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

Shaurova

Battaglia

et al. 2020

Cancers

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“…Recently, the identification of epidermal growth factor receptor (EGFR) mutations as oncogenic drivers has launched the era of precision medicine in the treatment of non-small cell lung cancer (NSCLC). A majority of patients who carry EGFR-sensitive mutations, such as exon 19 deletions (del 19) and exon 21 L858R substitutions, have benefited from the clinical application of gefitinib (37,38). However, some patients eventually develop acquired drug resistance during treatment, and thus, the efficacy is limited.…”

Section: Discussionmentioning

confidence: 99%

The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer

Sun

Liu

et al. 2020

Oncol Rep

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Gefitinib is currently the preferred treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutation. However, some patients gradually develop acquired resistance after receiving treatment. In addition to secondary T790M mutation, the remaining mechanisms contributing to non-T790M mutations need to be explored. In the present study, NSCLC-derived HCC827 and PC-9 cells and the corresponding gefitinib-resistant cell lines (HCC827GR and PC9GR) were utilized. Next-generation DNA sequencing was performed on the HCC827GR and PC9GR cells. Under AXL receptor tyrosine kinase (AXL) knockdown or miR-625-3p overexpressing conditions, a cell growth inhibition assay was performed to evaluate gefitinib sensitivity. Wound healing and Transwell assays were used to examine the migratory and invasive abilities of the cells. Moreover, we also carried out western blot analysis to detect the altered downstream signaling pathway. Our study revealed markedly decreased miR-625-3p expression in the HCC827GR cell line, while its overexpression partly reversed gefitinib resistance. Integrated analysis based on Targetscan website showed that AXL can be potentially targeted by miR-625-3p and we further verified the hypothesis via dual-luciferase reporter assays. Mechanistic analysis revealed that TGF-β1-induced EMT may contribute to the miR-625-3p/AXL axis-mediated gefitinib resistance. Our data demonstrated that miR-625-3p contributes to the acquired resistance of gefitinib, which may provide novel insight to combat resistance to EGFR-TKIs.Abbreviations: NSCLC, non-small cell lung cancer; TGF-β1, transforming growth factor-β1; HCC827GR, HCC827 gefitinib resistant; EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors; EMT, epithelial to mesenchymal transition

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“…A phase I dose-escalation study of osimertinib combined with necitumumab, a humanized EGFR monoclonal antibody, is underway for patients who progressed on previous first-line TKI therapy (NCT02789345). Recent work demonstrates that amplification of EGFR wild-type alleles can confer resistance to EGFR TKIs (34). By binding to extracellular domain of the EGFR receptor and competing with ligand binding, downsteam signaling leads to impaired tumor cell growth.…”

Section: Combinational Strategies With Osimertinibmentioning

confidence: 99%

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

et al. 2019

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EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a thirdgeneration tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.

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Amplification of EGFR Wild-Type Alleles in Non–Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors

Cited by 136 publications

References 49 publications

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

The miR‑625‑3p/AXL axis induces non‑T790M acquired resistance to EGFR‑TKI via activation of the TGF‑β/Smad pathway and EMT in EGFR‑mutant non‑small cell lung cancer

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer

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