Fig. 4: Genome doubling permits elevated ploidy and promotes multiple avenues to therapy resistance in the presence of p53 pathway dysfunction.

a Plot showing the number of resistant subclones generated from each of the 24 triploid and 24 hexaploid progenitor clones after 5 weeks of culture in 1.5 μM erlotinib. b Number of triploid (blue) and hexaploid (red) progenitor PC9 clones that generated at least one erlotinib-resistant subclone (p = 0.0346, chi-squared test). c Left panel: Presence of somatic mutations in genes related to the EGFR pathway (black squares) is reported across all triploid (upper blue row) and hexaploid (upper red row) resistant daughter clones derived from either triploid (lower blue row) or hexaploid (lower red row) parental clones. Right panel: Ploidy-relative copy-number gains (red colors) are reported for resistant daughter clones that have changed their ploidy state for 13 genes whose gain is known to have a role in TKI resistance. d Frequency of copy-number gains (positive y-axis) and losses (negative y-axis) are reported across either triploid (blue) or hexaploid (red) resistant daughter clones, highlighting events affecting oncogenes and tumor suppressors. e Clone-to-clone diversity measured by computing the copy-number difference (fraction of genome with different copy numbers reported in blue colors) between either left all pairs of triploid and hexaploid resistant daughter clones derived from the same parental clone (triangles), or right all pairs of triploid and hexaploid resistant daughter clones. f Impact of siRNA mediated repression of gained genes on re-sensitization of erlotinib-resistant hexaploid PC9 subclones. By factoring in effects on viability, the effect of gene silencing on erlotinib resistance was scored. Tiles corresponding to genes exhibiting a significant treatment-varying response upon knockdown (p < 0.05) in a hexaploid subclone are colored. Hue corresponds to the direction of change, and brightness to the erlotinib treatment status. Gene names depicted in bold did not impact parental PC9 viability. g Model depicting factors contributing to tumor resistance in E and EP tumors. Source data are provided as a Source Data file.