MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

Cancer Cell. 2022 Oct 10;40(10):1128-1144.e8. doi: 10.1016/j.ccell.2022.08.015.

Shunsuke Kitajima ¹, Tetsuo Tani ², Benjamin F Springer ³, Marco Campisi ², Tatsuya Osaki ⁴, Koji Haratani ², Minyue Chen ⁵, Erik H Knelson ², Navin R Mahadevan ⁶, Jessica Ritter ⁷, Ryohei Yoshida ², Jens Köhler ², Atsuko Ogino ², Ryu-Suke Nozawa ⁸, Shriram K Sundararaman ⁹, Tran C Thai ², Mizuki Homme ¹⁰, Brandon Piel ², Sophie Kivlehan ¹¹, Bonje N Obua ¹¹, Connor Purcell ¹², Mamiko Yajima ¹³, Thanh U Barbie ¹⁴, Patrick H Lizotte ¹¹, Pasi A Jänne ², Cloud P Paweletz ¹¹, Prafulla C Gokhale ³, David A Barbie ¹⁵

Affiliations

1 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, Japan. Electronic address: [email protected].
2 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA.
3 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
4 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.
5 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA.
6 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Pathology, Brigham and Women's Hospital, Boston, MA, USA.
7 Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
8 Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
9 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
10 Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo, Japan.
11 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
12 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA; Division of Biology and Medicine, Brown University, Providence, RI, USA.
13 Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
14 Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA; Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
15 Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA LC4115, USA. Electronic address: [email protected].

PMID: 36150391 DOI: 10.1016/j.ccell.2022.08.015

Abstract

KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient Mps1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.

Keywords

2’3’-cGAMP; DNMT1; EZH2; KRAS-LKB1 mutant lung adenocarcinoma; STING; cGAS; monopolar spindle kinase 1.

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Description

Target

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HY-108709

CC-671

99.06%, CDK Inhibitor

CDK

Cancer

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