Long-term IM resistance occurs via FGF2-dependent or -independent mechanisms, and FGF2-dependent resistance can be overcome by FGFR inhibition. (A-D) K562 cells with and without 10 ng/mL FGF2 and 2 long-term IM-resistant K562 outgrowths in 10 ng/mL FGF2 (Figure 1, denoted as K1 and K2) were exposed to a matrix of an IM gradient (0, 0.01, 0.04, 0.1, 0.4, 1.1, 3.3, 10 μM) combined with the FGFR inhibitor PD173074 (PD; 0, 0.001, 0.004, 0.01, 0.04, 0.11, 0.33, 1 μM). Viability was measured after 48 hours and average viability graphed as a surface plots using untreated as reference with colors denoting 20% increments. (E-H) Viability from surface plots indicating drug curves to IM (IM) alone, PD173074 alone, and combination to highlight synergy. Calculation of the combination index for relevant drug concentrations is included in supplemental Table 1. (I-L) K562 cells with and without 10 mg/mL FGF2, K1, and K2 in 10 mg/mL FGF2 were exposed to indicated concentrations of IM, DAS, NIL, and ponatinib (PON). Viability was measured after 48 hours. All experiments were done in triplicate with average viability scaled to untreated condition (100%). Error bars represent standard deviation.