Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma.

Blocking cancer genomic instability may prevent tumor diversification and escape from therapies. We show that, after MAPK inhibitor (MAPKi) therapy in patients and patient-derived xenografts (PDXs), acquired-resistant genomes of metastatic cutaneous melanoma specifically amplify resistance-driver, non-homologous end-joining (NHEJ), and homologous recombination repair (HRR) genes via complex genomic rearrangements (CGRs) and extrachromosomal DNAs (ecDNAs). Almost all sensitive and acquired-resistant genomes harbor pervasive chromothriptic regions with disproportionately high mutational burdens and significant overlaps with ecDNA and CGR spans. Recurrently, somatic mutations within ecDNA- and CGR-amplicons enrich for HRR signatures, particularly within acquired-resistant tumors. Regardless of sensitivity or resistance, breakpoint-sequence analysis suggests NHEJ as critical to double-stranded DNA break repair underlying CGR and ecDNA formation. In human melanoma cell lines and PDXs, NHEJ-targeting by a DNA-PKCS inhibitor prevents/delays acquired MAPKi resistance by reducing the size of ecDNAs and CGRs early on combination treatment. Thus, targeting the cause(s) of genomic instability prevents acquired resistance.