Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	20	4	2021 Apr	704-715	Mol Cancer Ther

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	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
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
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
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
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 + 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
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 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
FGFR2 amp	stomach cancer	predicted - sensitive	Futibatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lytgobi (futibatinib) treatment inhibited growth of gastric cancer cells harboring FGFR2 amplification in culture (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
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
FGFR1 over exp	stomach cancer	sensitive	Futibatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lytgobi (futibatinib) treatment inhibited growth of FGFR1-overexpressing gastric cancer cells in culture (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
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
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