First, a linear regression-based pharmacogenomic screen across four datasets (GDSC1, GDSC2, CTRP, CCLE; 1001 cell lines, 31 cancer types) identified 608 statistically significant (<i>p</i> < 0.01) mutational signature-drug interactions, revealing that UV-associated signature SBS7a is associated with broad-spectrum therapeutic resistance, including to BRAF inhibitors (PLX-4720, <i>p</i> < 10<sup>-4</sup>), while pollution-driven oxidative stress (SBS18) is associated with sensitivity to p38 MAPK inhibition (VX-702, r = -0.45, <i>p</i> < 10<sup>-9</sup>). Here, BRAF is linked to cancer.