Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer

Abstract

Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody-drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes.

Fig. 1 ∣. Genetic and transcriptomic landscape of SCLC.

a, Mutational landscape of small-cell lung cancer (SCLC). SCLC is characterized by an almost ubiquitous loss of TP53 and RB1. A substantial percentage of SCLCs also have amplification of MYC family members (MYC, MYCN and MYCL), and a smaller percentage harbour mutations in other genes, as shown. b, Evolution of SCLC transcriptional subtypes over time. The relative expression of key transcription factors is used to define subtypes within SCLC. This figure summarizes the chronology of preclinical studies that demonstrated the complexity of SCLC biology and evolution of these subtypes. NE, neuroendocrine.

Fig. 2 ∣. Heterogeneity, plasticity and evolution of SCLC.

a, Histological transformation of lung adenocarcinoma (LUAD) to small-cell lung cancer (SCLC) as a mechanism of acquired resistance to targeted therapy. LUADs harbouring a loss-of-function mutation in TP53 and/or RB1 can transform to a more aggressive neuroendocrine (NE) subtype of lung cancer resembling SCLC. This dynamic and complex process was first identified in patients with EGFR-mutant LUADs receiving tyrosine-kinase inhibitors (TKIs) and is accompanied by transcriptional and epigenetic reprogramming. b, Heterogeneity, plasticity and evolution of de novo SCLC. Studies from the past few years have demonstrated that SCLCs transform from one subtype to another (that is, from ASCL1-driven to NEUROD1-driven and YAP1-driven subtypes). MYC amplification and alterations affecting the Notch signalling pathway have a major role in subtype switching, transforming these tumours from NE to non-NE phenotypes. NE phenotypes tend to be less immunogenic and often tagged as immune ‘cold’, whereas YAP1-high SCLCs have better antigen presentation and response to immune checkpoint inhibitors.

Fig. 3 ∣. Translational roadmap for SCLC.

Integration of bedside-to-bench-to-bedside platforms to improve therapy and biomarker discovery in small-cell lung cancer (SCLC). New patients are diagnosed using pathology and imaging, and biospecimens (tissue and blood) are collected. The collected samples are then used to derive preclinical models that can be used in ‘wet-lab’ experiments to understand the biology of SCLC and identify novel therapies and biomarkers. These experiments are complemented with cutting edge computational analyses and artificial intelligence and/or machine learning approaches for ‘n-of-1’ studies and treatment selection. Patients then receive new drugs, and the response in overall survival, progression-free survival and other outcomes is monitored. CDX, circulating tumour cell-derived xenograft; PDX, patient-derived xenograft.

Fig. 4 ∣. Current management strategy for SCLC.

Proposed strategy for the management of patients with small-cell lung cancer (SCLC) as of 2024. ^aLimited-stage SCLC (LS-SCLC) includes stage I–III disease (T any, N any, M0) that can be safely treated with definitive radiation doses. Excludes T3–4 disease owing to the presence of multiple lung nodules that are too extensive or have tumour and/or nodal volume too large to be encompassed in a tolerable radiation plan. ^bExtensive-stage (ES-SCLC) includes stage IV (T any, N any, M 1a/b/c) and T3–4 disease. ^cDefined according to the Eighth Edition of TNM Staging of Lung Cancer. ^dIn patients with medically inoperable LS-SCLC who can be considered for stereotactic ablative radiotherapy or concurrent radiotherapy. ^eBased on the results from phase III ADRIATIC trial, not yet approved by the FDA.