Reference Detail

Ref Type

Journal Article

PMID

(35420673)

Authors

Wu Q, Zhen Y, Shi L, Vu P, Greninger P, Adil R, Merritt J, Egan R, Wu MJ, Yin X, Ferrone CR, Deshpande V, Baiev I, Pinto CJ, McLoughlin DE, Walmsley CS, Stone JR, Gordan JD, Zhu AX, Juric D, Goyal L, Benes CH, Bardeesy N

Title

EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	12	5	2022 May 02	1378-1395	Cancer Discov

URL

Abstract Text

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma.We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.

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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	intrahepatic cholangiocarcinoma	no benefit	Pemigatinib	Preclinical - Cell culture	Actionable	In a preclinical study, an intrahepatic cholangiocarcinoma cell line overexpressing FGFR1 was not sensitive to Pemazyre (pemigatinib) in culture (PMID: 35420673).	35420673
FGFR1 over exp	intrahepatic cholangiocarcinoma	no benefit	Futibatinib	Preclinical - Cell culture	Actionable	In a preclinical study, an intrahepatic cholangiocarcinoma cell line overexpressing FGFR1 was not sensitive to Lytgobi (futibatinib) in culture (PMID: 35420673).	35420673
FGFR1 over exp	intrahepatic cholangiocarcinoma	no benefit	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, an intrahepatic cholangiocarcinoma cell line overexpressing FGFR1 was not sensitive to Truseltiq (infigratinib) in culture (PMID: 35420673).	35420673