Dataset Information

Activation of CD44 / AKT signaling promotes resistance to FGFR1 inhibition in squamous cell lung cancer

ABSTRACT: Lung cancer is the leading cause of cancer related deaths, worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1, however, resistance mechanisms originally existing in patients or acquired throughout treatment have limited treatment efficiency in clinical trials, so far. In this study, we performed a wide-scale phosphoproteomic mass spectrometry analysis to explore signaling pathways that lead to FGFR1 inhibition resistance in lung cancer cells with intrinsic, induced and mutational resistance. We identified a CD44/AKT signaling axis as a new and common mechanism of resistance to FGFR1 inhibition in lung cancer. Co-inhibition of AKT or CD44 synergistically sensitized intrinsic and induced resistant cells to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated to AKT activation in squamous cell lung cancer patients. Collectively, our phosphoproteomic analysis of FGFR1 inhibitor resistant lung cancer cells promotes a large data library of resistance associated phosphorylation patterns and proposes a common resistance pathway consisting of CD44 and AKT activation. Examination of CD44/AKT activation could help to predict response to FGFR1 inhibition and combination with AKT inhibitors might path the way for an effective therapy of FGFR1 dependent lung cancer patients in case of treatment resistance.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Lung Cancer

SUBMITTER: Hanibal Bohnenberger

LAB HEAD: Hanibal Bohnenberger

PROVIDER: PXD025389 | Pride | 2022-08-12

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MQ-output_gPome.zip	Other
	MQ-output_pYome.zip	Other
	TO_Bohnenberger_151019_060120_phospho_R1_19-793.raw	Raw
	TO_Bohnenberger_151019_060120_phospho_R1_19-796.raw	Raw
	TO_Bohnenberger_151019_060120_phospho_R1_19-805.raw	Raw

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Publications

Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer.

Elakad Omar O Häupl Björn B Labitzky Vera V Yao Sha S Küffer Stefan S von Hammerstein-Equord Alexander A Danner Bernhard C BC Jücker Manfred M Urlaub Henning H Lange Tobias T Ströbel Philipp P Oellerich Thomas T Bohnenberger Hanibal H

NPJ precision oncology 20220719 1

Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1; however, resistance mechanisms originally existing in patients or acquired during treatment have so far led to limited treatment efficiency in clinical trials. In this study ...[more]

PMID: 35853934

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Project description:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.