Unravelling the biology of SCLC: implications for therapy

• Published in: Nature reviews. Clinical oncology Vol. 14; no. 9; pp. 549 - 561
• Main Authors: Sabari, Joshua K, Lok, Benjamin H, Laird, James H, Poirier, John T, Rudin, Charles M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2017
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; ASCL1 protein; Biology; Care and treatment; Cell death; Chemotherapy; Chromatin remodeling; Cytotoxicity; Genetic aspects; Genome; Histone-lysine N-methyltransferase; Humans; Immune checkpoint inhibitors; Immunotherapy; Immunotherapy - methods; Ligands; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphocytes; Lysine; Malignancy; Methyltransferase; Molecular Targeted Therapy - methods; Mutation; N-Methyltransferase; Notch protein; PD-1 protein; PD-L1 protein; Poly(ADP-ribose) polymerase; Prognosis; Proteomics; Ribose; Small cell lung cancer; Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Tumorigenesis
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/nrclinonc.2017.71

Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints.Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody-drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.