Inhibition of FGFR abrogates adaptive resistance to RET inhibitors in TPC1 cells. (A) Western blot analysis of FGFR1 and ERK activation and downstream signaling effectors in TPC1 cells treated with BLU6864 (RETi) alone or in combination with BGJ398 (FGFRi) over the indicated time course. (A) 24 + 1 timepoint indicates that the BGJ398 was added for 1 h after an initial incubation in BLU6864 for 24 h. (B) Western blot analysis of FGFR1 and ERK activation and downstream signaling effectors in TPC1 cells treated with XL184 alone or in combination with BGJ398 over the indicated time course. (A) 24 + 1 timepoint indicates that the BGJ398 was added for 1 h after an initial incubation in XL184 for 24 h. (C) Western blot analysis of ERK activation and downstream signaling effectors in TPC1 cells treated with XL184, BLU6864, and SHP099 alone or in combination. (D) Western blot analysis of FGFR1 and ERK activation in control infected TPC1 cells and in TPC1 cell clones isolated and expanded after lentiviral infection with sgRNAs targeting FGFR1 for genetic inactivation (FGFR1-KO1, FGFR1-KO2). Cells were treated with vehicle or BLU6864 for the indicated time and at a final concentration of 100 nM. For Western blots in A–D, a representative blot is shown from a minimum of three independent experiments.