Journal
NATURE REVIEWS CLINICAL ONCOLOGY
Volume 14, Issue 9, Pages 549-561Publisher
NATURE PORTFOLIO
DOI: 10.1038/nrclinonc.2017.71
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Funding
- National Cancer Institute [T32 CA009207, P30 CA008748, R01 CA197936]
- Conquer Cancer Foundation of ASCO
- Lung Cancer Research Foundation
- Radiological Society of North America
- National Cancer Institute [T32 CA009207, P30 CA008748, R01 CA197936]
- Conquer Cancer Foundation of ASCO
- Lung Cancer Research Foundation
- Radiological Society of North America
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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.
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