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Ref Type Journal Article
PMID (33563752)
Authors Lau DK, Luk IY, Jenkins LJ, Martin A, Williams DS, Schoffer KL, Chionh F, Buchert M, Sjoquist K, Boussioutas A, Hayes SA, Ernst M, Weickhardt AJ, Pavlakis N, Tebbutt NC, Mariadason JM
Title Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK.
Journal Molecular cancer therapeutics
Vol 20
Issue 4
Date 2021 Apr
URL
Abstract Text Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1-4 was detected in 8%-19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 over exp stomach cancer sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) treatment inhibited growth of FGFR1-overexpressing gastric cancer cells in culture (PMID: 33563752). 33563752
FGFR1 over exp stomach cancer sensitive Infigratinib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Mekinist (trametinib) restored sensitivity of gastric cancer cells with FGFR1 overexpression to Truseltiq (infigratinib) treatment, demonstrating decreased Erk phosphorylation and reduced cell proliferation in culture (PMID: 33563752). 33563752
FGFR1 over exp stomach cancer sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, treatment with Stivarga (regorafenib) in an FGFR1-overexpressing gastric cancer cell line resulted in decreased phosphorylation of Fgfr2 and Erk, and inhibition of cell growth in culture (PMID: 33563752). 33563752
FGFR3 fusion urinary bladder cancer sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, bladder cancer cell lines harboring an FGFR3 fusion were sensitive to treatment with Stivarga (regorafenib), demonstrating inhibition of cell growth (PMID: 33563752). 33563752
FGFR2 amp stomach cancer sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, treatment with Stivarga (regorafenib) in gastric cancer cell lines harboring FGFR2 amplification resulted in decreased phosphorylation of Fgfr2 and Erk, and inhibition of cell growth in culture (PMID: 33563752). 33563752
FGFR1 over exp stomach cancer sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) treatment inhibited growth of FGFR1-overexpressing gastric cancer cells in culture (PMID: 33563752). 33563752
FGFR2 amp stomach cancer sensitive Regorafenib + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of Mekinist (trametinib) restored sensitivity of gastric cancer cells with FGFR2 amplification to Stivarga (regorafenib) treatment, demonstrating decreased Erk phosphorylation and reduced cell proliferation in culture, and in cell line xenograft models led to inhibition of tumor growth (PMID: 33563752). 33563752
FGFR2 amp stomach cancer sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) inhibited growth of gastric cancer cell lines with FGFR2 amplification in culture (PMID: 33563752). 33563752
FGFR2 amp FGFR2 over exp stomach cancer no benefit Regorafenib Case Reports/Case Series Actionable In a Phase II trial, gastric cancer patients (n=3/35) with FGFR2 amplification and FGFR2 overexpression did not achieve an objective response when treated with Stivarga (regorafenib) (PMID: 33563752). 33563752
FGFR2 amp stomach cancer sensitive Infigratinib + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, the addition of Mekinist (trametinib) restored sensitivity of gastric cancer cells with FGFR2 amplification to Truseltiq (infigratinib) treatment, demonstrating decreased Erk phosphorylation and reduced cell proliferation in culture and inhibition of tumor growth in cell line xenograft models (PMID: 33563752). 33563752
FGFR2 amp colorectal cancer predicted - sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, a colorectal cancer cell line with FGFR1 and FGFR2 amplification was sensitive to treatment with Stivarga (regorafenib), demonstrating inhibition of cell growth in culture (PMID: 33563752). 33563752
FGFR1 over exp stomach cancer sensitive Regorafenib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Mekinist (trametinib) restored sensitivity of gastric cancer cells with FGFR1 overexpression to Stivarga (regorafenib) treatment, demonstrating decreased Erk phosphorylation and reduced cell proliferation in culture (PMID: 33563752). 33563752
FGFR1 amp FGFR2 amp breast cancer sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line with FGFR1 and FGFR2 amplification was sensitive to treatment with Stivarga (regorafenib), demonstrating inhibition of cell growth in culture (PMID: 33563752). 33563752
FGFR2 amp stomach cancer predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Futibatinib (TAS-120) treatment inhibited growth of gastric cancer cells harboring FGFR2 amplification in culture (PMID: 33563752). 33563752
FGFR1 over exp stomach cancer sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) treatment inhibited growth of gastric cancer cells overexpressing FGFR1 in culture (PMID: 33563752). 33563752