Comprehensive profiling of ALK fusion lung adenocarcinomas identifies mutant p53 driven DNA replication and repair deregulation in targeted therapy resistance [ChIP-Seq]

Here, we performed integrated genomic, transcriptomic, and single-cell analyses of clinical specimens and patient-derived xenografts (PDXs) to define previously uncharacterized mechanisms of resistance. Transcriptomic profiling revealed marked intratumoral heterogeneity, with multiple distinct and independent pathways contributing to ALK inhibitor resistance.

While secondary ALK mutations were detected in ~30% of resistant tumors, approximately half harbored no known actionable alterations. However, TP53 mutations, particularly DNA-binding domain missense variants, were significantly enriched in these TKI-resistant tumors and were associated with activation of DNA replication and repair programs. We find that missense mutant p53 acquired gain-of-function activity by directly binding promoters of replication and repair genes and engaging the chromatin remodeler EP400, thereby enhancing DNA damage repair and promoting survival under ALK inhibition.