Unravelling the biology of SCLC: implications for therapy

Key Points

  • Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumour associated with a poor overall survival, and limited progress has been made in the treatment of this disease over the past three decades

  • Over the past 5 years, advances in our understanding of multiple aspects of the biology of SCLC have led to the development of new therapies that are currently under clinical investigation

  • Poly [ADP-ribose] polymerase (PARP) is abundantly expressed in SCLC and is involved in DNA-damage repair; clinical trials of the PARP inhibitors veliparib, olaparib, and talazoparib are ongoing in patients with SCLC

  • Enhancer of zeste homologue 2 (EZH2) is a regulator of chromatin remodelling that can drive acquired chemoresistance; therapeutic targeting of EZH2 might augment and extend the durability of chemotherapy responses

  • Delta-like protein 3 (DLL3) is an inhibitory Notch ligand that is overexpressed in many SCLCs; rovalpituzumab tesirine (Rova-T), an anti-DLL3-antibody–drug conjugate, has shown promising activity in preclinical and early phase clinical studies

  • SCLC has a high mutational burden, raising hopes regarding immunotherapy, and immune-checkpoint blockade has shown encouraging clinical activity in patients with this disease, despite typically low tumoural expression of immune-checkpoint proteins

Abstract

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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Figure 1: Timeline of therapeutic advances for small-cell lung cancer (SCLC).
Figure 2: Signalling pathways and physiological domains that are the focus of experimental targeted therapies for small-cell lung cancer (SCLC).

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Acknowledgements

The work of the authors is supported by funding from the National Cancer Institute (grants T32 CA009207 to J.K.S., and P30 CA008748 and R01 CA197936 to C.M.R.), and from the Conquer Cancer Foundation of ASCO, the Lung Cancer Research Foundation, and the Radiological Society of North America (to B.H.L.).

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J.K.S. and B.H.L. made equal contributions to the manuscript and should be considered co-first authors. J.K.S., B.H.L., J.H.L., and J.T.P. researched data for article. All authors made substantial contributions to discussion of content, writing of the Review, and review/editing of the manuscript.

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Correspondence to John T. Poirier or Charles M. Rudin.

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C.M.R. has been a paid consultant regarding oncology drug development for Bristol-Myers Squibb, Celgene, G1 Therapeutics, Harpoon Therapeutics, Medivation, and Novartis. The other authors declare no competing interests.

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Sabari, J., Lok, B., Laird, J. et al. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol 14, 549–561 (2017). https://doi.org/10.1038/nrclinonc.2017.71

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