Taken together, our genome analyses show that TP53-damaging alterations associate with resistance to chemotherapy and that coexisting alterations of TP73, CREBBP/EP300 or FMN2 compromise the clinical efficacy of chemotherapy in patients with SCLC—even in the absence of gene-damaging TP53 alterations. The gene discussed is CREBBP; the disease is small cell lung carcinoma.