DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted June 11, 2021

Nabeel Bardeesy, Ph.D., Andrew Zhu, M.D., Ph.D., Lipika Goyal, M.D, Massachusetts General Hospital
Kevan Shokat, Ph.D., John Gordan, M.D., Ph.D. University of California, San Francisco

Nabeel Bardeesy, Ph.D., Massachusetts General Hospital Dr. Nabeel Bardeesy

Intrahepatic cholangiocarcinoma (ICC), also known as biliary cancer, is a rare malignancy of the liver bile ducts with limited treatment options, which often remains asymptomatic until advanced stage, resulting in poor prognosis. Fibroblast growth factor receptors (FGFR) play an important role in cell proliferation and differentiation. When genomic alterations, specifically point mutations, gene amplifications, or fusions, occur in FGFR that lead to cell signaling, they can initiate the development of a subset of liver (e.g., ICC), lung, stomach, and bladder cancers. Clinical trials with FGFR inhibitors (FGFRi) in advanced cholangiocarcinoma (e.g., infigratinib [BGJ398], NCT02150967 and pemigatinib, NCT02924376) showed significant benefit to patients whose tumors contained FGFR2 gene alternations.1,2 These results were unexpected and led to pemigatinib being the first targeted therapy approved by the Food and Drug Administration for the treatment of ICC, specifically in patients with FGFR2 fusions. Even with these promising results, resistance to FGFRi eventually develops in all patients. Thus, there is a current need to identify mechanisms of drug resistance and to develop approaches to overcome resistance in order to improve treatment options for biliary cancers.

Andrew Zhu, M.D., Ph.D., Massachusetts General Hospital Dr. Andrew Zhu

With a recently completed Fiscal Year 2016 Peer Reviewed Cancer Research Program Translation Team Science Award, Dr.Nabeel Bardeesy, in collaboration with Dr. Kevan Shokat, Dr. Andrew Zhu, Dr. Lipika Goyal, and Dr. John Gordan, sought to understand the basis for FGFRi response and resistance using patient samples and animal models, elucidate the signaling mechanisms controlled by FGFR2, and develop new strategies for preventing and overcoming treatment resistance in ICC. Analysis of blood and tumor samples from ICC patients treated with infigratinib or other FGFRi that eventually became resistant, revealed that FGFRi resistance is associated with a secondary mutation in the FGFR2 kinase domain in a subset of cases, whereas in other cases no acquired mutations are observed. In vitro analysis with ICC cell lines containing FGFR2 kinase domain mutations showed that the covalent, “next-generation” FGFRi, futibatinib (TAS-120), was able to overcome FGFRi resistance. Accordingly, patients who developed secondary FGFR2 kinase domain mutations as a mechanism of resistance to infigratinib showed clinical benefit of subsequent futibatinib treatment.

Kevan Shokat, Ph.D., University of California, San Francisco Dr. Kevan Shokat

Additional analysis using molecular techniques and patient-derived cell lines and xenografts demonstrated that so-called signaling feedback pathways limited the efficacy of FGFRi treatment in both models that are sensitive to FGFRi treatment or those that are resistant, but lack FGFR2 kinase domain mutations. FGFRi treatment led to a transient inhibition of downstream oncogenic pathways, with MEK/ERK and/or PI3K/AKT signaling showing strong rebound in activity over time. Accordingly, these adaptive changes limited the amount of cell death resulting from FGFR inhibition.

To further study FGFRi resistance observed in ICC patients, the team conducted combination drug screens. FGFR2 + ICC cells were treated with infigratinib in combination with a library of clinically relevant compounds, spanning kinase inhibitors, epigenetic drugs, metabolism-targeted compounds, and proteasome inhibitors. Combination of FGFRi and inhibitors of PI3K/AKT, the BCL2 pathway, and other receptor tyrosine kinases elicited cell death, which was not observed in the presence of a single agent of FGFRi. These discoveries suggest novel drug combination strategies that have the potential to increase the response rate to FGFRi and overcome adaptive resistance in ICC patients.

The proteogenomic investigation into FGFRi resistance and development of novel strategies for overcoming treatment resistance in ICC has not only given hope to patients burdened with this rare disease, but it also opens the door for potential therapeutics for lung, stomach, and bladder cancers that are also driven by FGFR signaling. The team has published their findings in Cancer Discovery,3,4,5 with additional manuscripts in preparation.

References:

1 Javle M, Lowery M, Shorff RT, et al. 2018. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. Journal of Clinical Oncology 36:276-282.

2 Silverman IM, Hollebecque A, Friboulet L, et al. 2021. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib. Cancer Discovery 11(2):326-339.

Publications:

3 Goyal L, Shi L, Liu LY, et al. 2019. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discovery 9(8):1064-1079.

4 Goyal L, Saha SK, Liu L, et al. 2017. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discovery 7(3):252-263.

5 Cleary JM, Raghavan S, Wu Q, et al. 2021. FGFR2 extracellular domain in-frame deletions are therapeutically targetable genomic alterations that function as oncogenic drivers in cholangiocarcinoma. Cancer Discovery 29:candisc.1669.2020.

Link:

Public and Technical Abstracts: A Proteomic Co-Clinical Trial of BGJ-398 in FGFR-Driven Biliary Cancers

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Last updated Friday, June 11, 2021