Editors' ChoiceCancer therapy

New connections: Targeted treatment options for SCLC

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Science Signaling  11 Feb 2020:
Vol. 13, Issue 618, eabb1864
DOI: 10.1126/scisignal.abb1864

Various studies reveal how we might effectively treat small cell lung cancer.

Patients with small cell lung cancer (SCLC) have few therapeutic options, and these are rarely curative. Therefore, identifying targeted therapeutics tailored to SCLC-specific molecular signatures is critical to improving clinical outcomes. In the Archives of Science Signaling, Augert et al. showed that inhibitors of the epigenetic enzyme LSD1 reactivated tumor-suppressive signaling in an aggressive subtype of SCLC, leading to durable tumor regression (shrinkage) in mice bearing patient-derived tumors. Few other molecular drivers of SCLC are known. Although the transcription factor and oncogene MYC is often overexpressed, it is difficult to therapeutically target. For this reason, exploring treatments that cause MYC protein degradation, such as inhibitors of the kinase CDK9 (see Blake et al. in the Archives), might be fruitful. Additional strategies may emerge from consideration of the tumor microenvironment. Immunotherapies, such as programmed cell death 1 (PD-1)–blocking antibodies that target the tumor’s suppression of associated immune cells, are approved for use in SCLC but have had limited benefit on patient survival. Immunotherapies generally only work in so-called “hot” tumors, where immune cells are actively infiltrating. Zhang et al. found that an inhibitor of CDK7 (called YKL-5-124) “turns up the heat” in SCLC to improve immunotherapeutic efficacy. In various models of SCLC, YKL-5-124 slowed the cell cycle and caused replicative stress and genomic instability, which triggered the secretion of various proinflammatory cytokines that recruited T cells into the tumors. Compared with either single agent alone, combining YKL5-124 with PD-1–blocking antibodies more durably reduced tumor growth and increased survival in mice bearing SCLC, and the effects were greatest when this duo was further combined with standard chemotherapy, without any overt general toxicity in the mice. These studies reveal paths being forged to new and, hopefully, improved treatment options for SCLC patients.

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