Our study thus establishes a critical role for the genomic context of the common ancestor in drug resistance, and we uncover its genomic portrait that is largely confined to biallelic losses of TP53 and RB1. Gene-damaging alterations in TP53 associate with a particularly chemotherapy-resistant state in patients with SCLC, which is in line with studies establishing a role of functionally distinct TP53 alterations impacting the response to chemotherapy and clinical outcome in cancer36–38. The gene discussed is TP53; the disease is small cell lung carcinoma.