Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway

Lü, Yuhong; Liu, Yanfeng; Oeck, Sebastian; Zhang, Gary J.; Schramm, Alexander; Glazer, Peter M.

doi:10.1158/0008-5472.can-20-1192

Cited by 60 publications

(49 citation statements)

References 45 publications

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“… 20 A recent study shows that hypoxia-induced resistance to osimertinib is driven by overexpression of fibroblast growth factor receptor 1 (FGFR1) to sustain ERK signaling and subsequent attenuation of Bim induction, which can be overcome by combining with an FGFR1 or MEK inhibitor. 21 In agreement, other studies, albeit with different rationales, also demonstrate a critical role of functional Bim in mediating apoptosis induced by osimertinib, other third-generation EGFR-TKIs or the combination of osimertinib with other agents in EGFR-mutant NSCLC cells. 22–26 …”

Section: Introductionsupporting

confidence: 70%

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Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

Yu¹,

Zhao²,

Vallega³

et al. 2021

LCTT

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Although epidermal growth factor receptor (EGFR)-targeted therapy has improved clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) carrying activating EGFR mutations, the development of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including the promising third-generation ones, results in disease progression and has become an unavoidable problem that limits patient long-term benefit. The third-generation EGFR-TKIs, osimertinib and almonertinib, are now approved for the treatment of advanced NSCLC patients harboring activating EGFR mutations (first-line) and/or the resistant T790M mutation (second-line). Clinically, appropriate management of acquired resistance to third-generation EGFR-TKIs will substantially improve their long-term efficacy against EGFR-mutant NSCLC. Recent preclinical and clinical studies suggest that activation of the Ras/Raf/MEK/ERK signaling pathway may be an important resistance mechanism and accordingly co-targeting this pathway effectively overcomes and abrogates acquired resistance to third-generation EGFR-TKIs. This review focuses on discussing the scientific rationale for and potential of co-targeting MEK/ERK signaling in delaying and overcoming acquired resistance to third-generation EGFR-TKIs, particularly osimertinib.

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Section: Introductionsupporting

confidence: 70%

“… 40 Beyond the RAS-dependent resistance models, MEK inhibition with trametinib synergized with osimertinib to suppress the growth of EGFR-mutant NSCLCs expressing a B-Raf fusion 45 or resistant tumors with elevated expression of FGFR1 and activated MEK/ERK signaling. 21 …”

Section: Introductionmentioning

confidence: 99%

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

Yu¹,

Zhao²,

Vallega³

et al. 2021

LCTT

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“…In another model, NSCLC cell lines with EGFR alterations (including T790M mutation, sensitizing to Osimertinib) were exposed to Osimertinib with a chronic and moderate hypoxic atmosphere. Interestingly, hypoxic NSCLC cell lines developed a resistance associated with a mesenchymal polarization and supported by FGFR1 (fibroblast growth factor receptor 1), largely resulting from mitogen-activated protein kinases (MAPK) pathway activation [ 129 ].…”

Section: Biological Features Associated With Hypoxia In Nsclcmentioning

confidence: 99%

Hypoxia in Lung Cancer Management: A Translational Approach

Ancel

Perotin

Dewolf

et al. 2021

Cancers

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Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management.

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“…In addition, one study has reported that microRNAs, metabolic pathways, and pseudohypoxia initiate drug tolerance to EGFR inhibitors in lung adenocarcinoma (47). Lu et al demonstrated that prolonged, long-term, moderate hypoxia can promote resistance to the third-generation EGFR-TKI osimertinib (AZD9291) in the NSCLC cell line H1975 that had developed resistance to firstand second-generation EGFR-TKIs via the T790M EGFR mutation (43,48). Hypoxia exposure induces gefitinib resistance in both EGFR-wild type and EGFRmutated NSCLC through epigenetic changes and regulation of epithelial-mesenchymal transition (EMT) (49)(50)(51).…”

Section: Hypoxia-induced Chemotherapy Resistance In Nsclcmentioning

confidence: 99%

“…Recent experiments using tumor cell lines also support that hypoxia-induced HIF-1α can increase PD-L1 expression on tumor cells, via direct interaction with a hypoxia-response element in the PD-L1 proximal promoter to activate transcription ( 42 ). Hypoxia may also be an important mediator of resistance to EGFR-TKIs via the upregulation of FGFR1 and the MAPK pathway in the NSCLC cell line H1975 ( 43 ).…”

Section: Hypoxia-induced Chemotherapy Resistance In Nsclcmentioning

confidence: 99%

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

Luo

et al. 2021

Front. Oncol.

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Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.

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Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway

Cited by 60 publications

References 45 publications

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

Hypoxia in Lung Cancer Management: A Translational Approach

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

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