The evolutionary changes of small cell lung cancer under therapy

Evolutionary trajectories of small cell lung cancer (SCLC) under therapy have been uncovered by a thorough genomic analysis recently published on Nature, showing genomic patterns associated with sensitivity and resistance to chemotherapy.

Despite progress in characterization of the molecular basis of SCLC, the underlying patterns of clonal evolution and the mechanisms causing drug resistance have remained unclear. Ipothesizing that cancer genome alterations influence the clinical phenotypes of chemotherapy sensitivity, tumour progression and relapse, authors determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Results showed a clonal homogeneity at distinct tumor sites in treatment-naive SCLC, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. A shift to ancestral clones was underlying tumour relapse and effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. «New drugs are typically tested in the second or third line of treatment, almost always with limited efficacy. We speculate that this phenomenon may be due, at least partially, to the massive increase in clonal heterogeneity following first-line chemotherapy», authors say. «Despite the overall short time window of clinical care, effective treatment—including radiation or successful immunotherapy—can accelerate the emergence of ancestral clones with platinum-induced genomic scars that subsequently cause relapse». These data put the most recent common ancestral clone at the centre of cancer genome evolution and as researchers conclude «emphasize the need for future therapeutic strategies to be tailored to target the detrimental cellular component of the founder clone to improve the outcome of patients with SCLC».