Abstract
The overall goal of this study was to elucidate the role of FGFR1 induction in acquired resistance to MET and VEGFR2 inhibition by cabozantinib in prostate cancer (PCa) and leverage this understanding to improve therapy outcomes. The response to cabozantinib was examined in mice bearing patient-derived xenografts in which FGFR1 was overexpressed. Using a variety of cell models that reflect different PCa disease states, the mechanism underpinning FGFR1 signaling activation by cabozantinib was investigated. We performed parallel investigations in specimens from cabozantinib-treated patients to confirm our in vitro and in vivo data. FGFR1 overexpression was sufficient to confer resistance to cabozantinib. Our results demonstrate transcriptional activation of FGF/FGFR1 expression in cabozantinib-resistant models. Further analysis of molecular pathways identified a YAP/TBX5-driven mechanism of FGFR1 and FGF overexpression induced by MET inhibition. Importantly, knockdown of YAP and TBX5 led to decreased FGFR1 protein expression and decreased mRNA levels of FGFR1, FGF1, and FGF2. This association was confirmed in a cohort of hormone-naïve patients with PCa receiving androgen deprivation therapy and cabozantinib, further validating our findings. These findings reveal that the molecular basis of resistance to MET inhibition in PCa is FGFR1 activation through a YAP/TBX5-dependent mechanism. YAP and its downstream target TBX5 represent a crucial mediator in acquired resistance to MET inhibitors. Thus, our studies provide insight into the mechanism of acquired resistance and will guide future development of clinical trials with MET inhibitors.
Highlights
Prostate cancer (PCa) is a leading cause of cancer morbidity and mortality in men worldwide, with an estimated 174,650 new cases and 31,620 deaths in 2019 in the United States [1]
We recently showed that FGFR1 was increased upon long-term treatment of patient-derived xenografts (PDXs) with cabozantinib, and knockdown of MET in cell lines increased FGFR1 expression [8]
The present study aims to examine the role of FGFR1 expression and activation in acquired resistance to MET/VEGFR2 inhibition by cabozantinib in prostate cancer (PCa), demonstrate whether an FGF/FGFR1 autocrine loop serves as a compensatory mechanism for cell survival, and determine the role of Yes-associated protein (YAP)
Summary
Prostate cancer (PCa) is a leading cause of cancer morbidity and mortality in men worldwide, with an estimated 174,650 new cases and 31,620 deaths in 2019 in the United States [1]. Cancers 2020, 12, 244; doi:10.3390/cancers12010244 www.mdpi.com/journal/cancers (RTKs) are overexpressed in mCRPC and predictive of poor prognosis [3], inhibitors of RTKs (Tyrosine kinase inhibitors, TKIs), such as c-MET (mesenchymal to epithelial transition, proto-oncogene), VEGFR2. A recent example of the difficulty in translating murine investigations into clinically meaningful responses is cabozantinib, an oral multikinase inhibitor with potent activity against phospho-MET and phospho-VEGFR2, which demonstrated clinical and radiological responses in patients with CRPC with bone metastasis [4]. Despite efficacy in individual patients, a phase III trial in unselected patients failed to demonstrate a survival benefit [5]. These findings can be explained by the fact that several tyrosine kinases can drive tumor progression in patients with CRPC. Elucidating the mechanisms of resistance to TKIs and leveraging that understanding to develop strategies to overcome the resistance will be of clinical significance
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