The investigators used two bladder cancer cell lines that harbor FGFR3 fusions (RT4 and SW780) resistant through continuous culture in the FGFR inhibitor BGJ398. These cells also exhibited cross-resistance to other types of FGFR inhibitors, indicating that the observed mechanisms for resistance are a class effect. To investigate whether this could be related to crosstalk with other receptor tyrosine kinases (RTKs), Weickhardt et al. conducted a screen on 49 RTKs. They found an increase in phosphorylation of ERBB3 in both resistant cell lines. Cell growth was synergistically inhibited after treatment with the FGFR inhibitor in combination with a pan-ERBB family inhibitor AZD8391. Cell cycle dynamics were also altered, showing a significant reduction in the proportion of cells in the S phase and a significant increase in the proportion of cells in G0 or G1. These effects persisted even when the dose of FGFR inhibitor was 10- or 20-fold less than the dose used to generate resistance.
The resistant cell lines also exhibited a rapid response to the FGFR inhibitors in the acute phase, as levels of pERBB3 increased over the first 24 hours. This rapid response was also attenuated by combined treatment with the FGFR inhibitor and pan-ERBB inhibitor. The effects were synergistic, and the cell cycle was altered as in long-term resistance. Moreover, cell proliferation was synergistically suppressed in the resistant bladder cell lines upon combination treatment with FGFR inhibitor and pan-ERBB inhibitor.
These findings are valuable for our understanding of resistance mechanisms. Unlike inherent resistance, acquired resistance can be targeted if the altered molecular players and pathways are elucidated. Interestingly, cells that harbor FGFR mutations or translocations show the ability to switch their dependence to ERBB family members for growth, which may help explain why combined treatment with a pan-ERBB inhibitor shows synergistic effectiveness in inhibiting cell growth and proliferation. One limitation of the study is that it was performed in vitro using two cell lines. Therefore, follow-up studies should test these observations in vivo and patient-derived samples.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York
References:
- Weickhardt, A.J., Lau, D.K., Hodgson-Garms, M. et al. Dual targeting of FGFR3 and ERBB3 enhances the efficacy of FGFR inhibitors in FGFR3 fusion-driven bladder cancer. BMC Cancer 22, 478 (2022). https://doi.org/10.1186/s12885-022-09478-4
Read the Abstract