Fig. 1: Drug resistance promotes collateral sensitivity to MCB-613 in EGFR-mutant NSCLC.

a Relative cell viability following 72-h incubation with gefitinib across 8-point serial drug dilution. Data are mean ± SEM for n = 3 biologically independent experiments. b High-throughput pharmacologic screening strategy. c Manhattan plot depicting results of chemical screen. Each point represents the average of (resistant - parental) from two biologically independent experiments. Collateral resistances and sensitivities in red and blue, respectively. All other conditions (no collateral effect, empty control wells, vehicle control wells) gray. Dotted horizontal lines indicate thresholds for collateral resistances (top, y = 0.3) and sensitivities (bottom, y = −0.3). d Magnification of Manhattan plot highlighting MCB-613. e Relative cell viability following 72-h incubation with 1.75 μM MCB-613. Data are mean ± SEM for n = 3 biologically independent experiments. P values computed using one-way ANOVA with multiple comparisons. Exact p values listed within Source Data. f Relative cell viability of parental and gefitinib-resistant PC9 clones following 72-h incubation with 4 µM MCB-613. Data are mean ± SEM for n = 3 biologically independent experiments. P values computed using one-way ANOVA with multiple comparisons. g. Relative cell viability of parental and gefitinib-resistant HCC827 clones following 72-h incubation with 2 µM MCB-613. Data are mean ± SEM of n = 3 biologically independent experiments. P values computed using one-way ANOVA with multiple comparisons. h Relative cell viability of parental and osimertinib-resistant cells following 72-h incubation with MCB-613 across 8-point linear drug dilution. Data are mean ± SEM for n = 3 biologically independent experiments. i Tumor growth curves from mice xenotransplanted with PC9 or GR4 cells and treated with vehicle (saline) or MCB-613 (20 mg/kg) three times weekly via interaperitoneal injection. Data are mean ± SEM for n = 10 mice. P values computed using one-way ANOVA with multiple comparisons. j Line plot depicting estimated cumulative cell growth over time in vitro for a heterogeneous population comprised of 97% drug-naïve PC9 cells and 3% drug-resistant cells (1% PFR3, 1% GR4, 1% WZR12) exposed to either gefitinib, MCB-613, or combination of the two. Data are mean ± SEM for n = 3 biologically independent experiments. Source data are provided as a Source Data file.