This study investigates the evolutionary trajectories of small cell lung cancer (SCLC) under therapy. Using multiregion sequencing of 160 tumours from 65 patients, the researchers determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy. They found that treatment-naive SCLC exhibited clonal homogeneity, but first-line platinum-based chemotherapy led to increased genomic intratumour heterogeneity and spatial clonal diversity. Branched evolution and a shift to ancestral clones were observed, with effective radio- or immunotherapy re-expanding founder clones with acquired genomic damage from first-line chemotherapy. TP53 and RB1 alterations were part of the common ancestor, while MYC family amplifications were not. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours with clonal CREBBP/EP3OO alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations with TP73, CREBBP/EP3OO or FMN2 were significantly associated with shorter disease relapse following chemotherapy. SCLC is one of the deadliest human cancers, with a 5-year survival rate of less than 7%. The standard of care for extensive-stage SCLC includes platinum and etoposide, recently combined with PD-L1 immune checkpoint inhibitors. SCLC is typically highly sensitive to platinum-based chemotherapy but rapidly recurs, distinguishing it from most other cancers. Second-line treatment is only marginally effective, and patients ultimately succumb to their disease. Previous genome sequencing studies of SCLC showed universal biallelic losses of TP53 and RB1, additional alterations to histone-modifying enzymes and cell cycle regulators, and MYC transcription factor amplifications. SCLC subgroups were defined based on the expression of neuroendocrine lineage transcription factors, which impact tumour biology and treatment outcome. Preliminary studies have provided initial clues in regard to molecular pathways associated with resistance to chemotherapy. Despite progress in characterizing the molecular basis of SCLC, the underlying patterns of clonal evolution and mechanisms causing drug resistance remain unclear. The study suggests that cancer genome alterations not only drive malignant transformation in SCLC but also influence clinical phenotypes of chemotherapy sensitivity, tumour progression and relapse. The researchers performed comprehensive multiregional and longitudinal studies of tumours from 65 patients to decipher the evolutionary and genomic principles governing response and resistance to therapy in SCLC. They collected 160 tumour specimens from 65 patients with SCLC, performed whole-exome, genome and transcriptome sequencing, and analyzed at least two tumour samples per patient. They identified tumour phylogenies for all 65 patients, showing patterns of linear and branched evolution, with some indicating sequential acquisition of genome alterations and others showing branched evolution from ancestral clones. The study found that the common ancestor was theThis study investigates the evolutionary trajectories of small cell lung cancer (SCLC) under therapy. Using multiregion sequencing of 160 tumours from 65 patients, the researchers determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy. They found that treatment-naive SCLC exhibited clonal homogeneity, but first-line platinum-based chemotherapy led to increased genomic intratumour heterogeneity and spatial clonal diversity. Branched evolution and a shift to ancestral clones were observed, with effective radio- or immunotherapy re-expanding founder clones with acquired genomic damage from first-line chemotherapy. TP53 and RB1 alterations were part of the common ancestor, while MYC family amplifications were not. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours with clonal CREBBP/EP3OO alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations with TP73, CREBBP/EP3OO or FMN2 were significantly associated with shorter disease relapse following chemotherapy. SCLC is one of the deadliest human cancers, with a 5-year survival rate of less than 7%. The standard of care for extensive-stage SCLC includes platinum and etoposide, recently combined with PD-L1 immune checkpoint inhibitors. SCLC is typically highly sensitive to platinum-based chemotherapy but rapidly recurs, distinguishing it from most other cancers. Second-line treatment is only marginally effective, and patients ultimately succumb to their disease. Previous genome sequencing studies of SCLC showed universal biallelic losses of TP53 and RB1, additional alterations to histone-modifying enzymes and cell cycle regulators, and MYC transcription factor amplifications. SCLC subgroups were defined based on the expression of neuroendocrine lineage transcription factors, which impact tumour biology and treatment outcome. Preliminary studies have provided initial clues in regard to molecular pathways associated with resistance to chemotherapy. Despite progress in characterizing the molecular basis of SCLC, the underlying patterns of clonal evolution and mechanisms causing drug resistance remain unclear. The study suggests that cancer genome alterations not only drive malignant transformation in SCLC but also influence clinical phenotypes of chemotherapy sensitivity, tumour progression and relapse. The researchers performed comprehensive multiregional and longitudinal studies of tumours from 65 patients to decipher the evolutionary and genomic principles governing response and resistance to therapy in SCLC. They collected 160 tumour specimens from 65 patients with SCLC, performed whole-exome, genome and transcriptome sequencing, and analyzed at least two tumour samples per patient. They identified tumour phylogenies for all 65 patients, showing patterns of linear and branched evolution, with some indicating sequential acquisition of genome alterations and others showing branched evolution from ancestral clones. The study found that the common ancestor was the