Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1

Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype...

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Published in:Cell reports. Medicine 2023-11, Vol.4 (11), p.101282, Article 101282
Main Authors: Li, Yixiang, Mahadevan, Navin R, Duplaquet, Leslie, Hong, Deli, Durmaz, Yavuz T, Jones, Kristen L, Cho, Hyeonseo, Morrow, Murry, Protti, Andrea, Poitras, Michael J, Springer, Benjamin F, Bronson, Roderick T, Gong, Xueqian, Hui, Yu-Hua, Du, Jian, Southard, Jackson, Thai, Tran, Li, Shuqiang, Lizotte, Patrick H, Gokhale, Prafulla C, Nguyen, Quang-De, Oser, Matthew G
Format: Article
Language:English
Subjects:
Animals
Aurora Kinase A - genetics
Aurora Kinase A - therapeutic use
B7-H1 Antigen - genetics
Humans
Interferons - genetics
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Mice
Mitosis
Small Cell Lung Carcinoma - drug therapy
Small Cell Lung Carcinoma - genetics
Small Cell Lung Carcinoma - pathology
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Summary:Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2023.101282