Data from Resistance to Selective FGFR Inhibitors in <i>FGFR-</i>Driven Urothelial Cancer

Abstract

<div>Abstract<p>Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of <i>FGFR</i>-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with <i>FGFR</i>-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K–mTOR pathway (<i>n</i> = 4 <i>TSC1/2</i>, <i>n</i> = 4 <i>PIK3CA</i>, <i>n</i> = 1 <i>TSC1</i> and <i>PIK3CA</i>, <i>n</i> = 1 <i>NF2</i>, <i>n</i> = 1 <i>PTEN</i>). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib–gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.</p>Significance:<p>In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K–mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0728" target="_blank">See related commentary by Tripathi et al., p. 1964.</a></i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-9-ITI" target="_blank">This article is featured in Selected Articles from This Issue, p. 1949</a></i></p></div>