Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

Abstract

Endometrial cancer is the most commonly diagnosed gynaecological malignancy. Unfortunately, 15–20% of women demonstrate persistent or recurrent tumours that are refractory to current chemotherapies. We previously identified activating mutations in fibroblast growth factor receptor 2 ( FGFR 2) in 12% (stage I/ II ) to 17% (stage III / IV ) endometrioid EC s and found that these mutations are associated with shorter progression‐free and cancer‐specific survival. Although FGFR inhibitors are undergoing clinical trials for treatment of several cancer types, little is known about the mechanism by which they induce cell death. We show that treatment with BGJ 398, AZD 4547 and PD 173074 causes mitochondrial depolarization, cytochrome c release and impaired mitochondrial respiration in two FGFR 2‐mutant EC cell lines ( AN 3 CA and JHUEM 2). Despite this mitochondrial dysfunction, we were unable to detect caspase activation following FGFR inhibition; in addition, the pan‐caspase inhibitor Z‐ VAD ‐ FMK was unable to prevent cell death, suggesting that the cell death is caspase‐independent. Furthermore, while FGFR inhibition led to an increase in LC 3 puncta, treatment with bafilomycin did not further increase lipidated LC 3, suggesting that FGFR inhibition led to a block in autophagosome degradation. We confirmed that cell death is mitochondrial‐dependent as it can be blocked by overexpression of Bcl‐2 and/or Bcl‐ XL . Importantly, we show that combining FGFR inhibitors with the BH 3 mimetics ABT 737/ ABT 263 markedly increased cell death in vitro and is more effective than BGJ 398 alone in vivo , where it leads to marked tumour regression. This work may have implications for the design of clinical trials to treat a wide range of patients with FGFR ‐dependent malignancies.

Futibatinib, an Irreversible FGFR1–4 Inhibitor, in Patients with Advanced Solid Tumors HarboringFGF/FGFRAberrations: A Phase I Dose-Expansion Study

“…Of the 2 patients with objective responses, one had an FGFR2 p.W290C mutation and the other had an FGFR2 p.C383R mutation (also known as a p.C382R mutation in an alternative transcript (17). These mutations, in the extracellular domain (p.W290C) and in the transmembrane domain (p.C383R), have been classified as pathogenic or activating in the ClinVar database and have been shown to be sensitive to FGFR inhibitors in preclinical experiments (32)(33)(34)(35). Notably, in the phase II trial of pemigatinib, 3 of 4 patients with tumors harboring p.C382R mutations achieved tumor stability with PFS ranging from 4.0 to 9.0 months (17), also suggesting the potential actionability of these alterations.…”

BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer

“…10 Cell Reports 38, 110374, February 15, 2022 Article ll OPEN ACCESS inhibition (Packer et al, 2019;Turunen et al, 2019;Weeden et al, 2018). In breast cancer cells, A-1155463 was found to significantly potentiate BLU9931-induced cell death in a study examining the role of FGFR4-mediated resistance, indicating broader applicability of this combination strategy in solid tumors (Turunen et al, 2019).…”

Biological Significance and Targeting of the FGFR Axis in Cancer

“…However, they did not detect caspase activation following FGFR inhibition. When they were treated with the pan-caspase inhibitor (Z-VAD-FMK) they did not prevent cell death, suggesting that the cell death was caspase-independent [247]. Bcl-2 inhibitors enhanced FGFR inhibitor-induced mitochondrial-dependent endometrial cancer cell death [247].…”

“…When they were treated with the pan-caspase inhibitor (Z-VAD-FMK) they did not prevent cell death, suggesting that the cell death was caspase-independent [247]. Bcl-2 inhibitors enhanced FGFR inhibitor-induced mitochondrial-dependent endometrial cancer cell death [247]. Interestingly, in another study, Infigratinib induced cell death in nonsmall cell lung cancer cells (H1581) by activating the caspase-dependent mitochondrial and non-mitochondrial pathway [239].…”