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

Yixiang Li; Navin R Mahadevan; Leslie Duplaquet; Deli Hong; Yavuz T Durmaz; Kristen L Jones; Hyeonseo Cho; Murry Morrow; Andrea Protti; Michael J Poitras; Benjamin F Springer; Roderick T Bronson; Xueqian Gong; Yu-Hua Hui; Jian Du; Jackson Southard; Tran Thai; Shuqiang Li; Patrick H Lizotte; Prafulla C Gokhale; Quang-De Nguyen; Matthew G Oser

doi:10.1016/j.xcrm.2023.101282

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

Cell Rep Med. 2023 Nov 21;4(11):101282. doi: 10.1016/j.xcrm.2023.101282.

Authors

Yixiang Li¹, Navin R Mahadevan², Leslie Duplaquet¹, Deli Hong¹, Yavuz T Durmaz¹, Kristen L Jones³, Hyeonseo Cho¹, Murry Morrow³, Andrea Protti³, Michael J Poitras⁴, Benjamin F Springer⁴, Roderick T Bronson⁵, Xueqian Gong⁶, Yu-Hua Hui⁶, Jian Du⁶, Jackson Southard⁷, Tran Thai¹, Shuqiang Li⁷, Patrick H Lizotte⁸, Prafulla C Gokhale⁴, Quang-De Nguyen³, Matthew G Oser⁹

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
⁵ Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215, USA.
⁶ Loxo@Lilly, Indianapolis, IN 46225, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Translational Immunogenomics Lab, Dana Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

Abstract

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.

Keywords: ASCL1; Aurora A kinase; M phase; MHC class I; PD-L1; antigen presentation; interferon; mitosis; small cell lung cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

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

Substances

CD274 protein, human
B7-H1 Antigen
Aurora Kinase A
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding