MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

Shunsuke Kitajima; Tetsuo Tani; Benjamin F Springer; Marco Campisi; Tatsuya Osaki; Koji Haratani; Minyue Chen; Erik H Knelson; Navin R Mahadevan; Jessica Ritter; Ryohei Yoshida; Jens Köhler; Atsuko Ogino; Ryu-Suke Nozawa; Shriram K Sundararaman; Tran C Thai; Mizuki Homme; Brandon Piel; Sophie Kivlehan; Bonje N Obua; Connor Purcell; Mamiko Yajima; Thanh U Barbie; Patrick H Lizotte; Pasi A Jänne; Cloud P Paweletz; Prafulla C Gokhale; David A Barbie

doi:10.1016/j.ccell.2022.08.015

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. Epub 2022 Sep 22.

Authors

Shunsuke Kitajima¹, Tetsuo Tani², Benjamin F Springer³, Marco Campisi², Tatsuya Osaki⁴, Koji Haratani², Minyue Chen⁵, Erik H Knelson², Navin R Mahadevan⁶, Jessica Ritter⁷, Ryohei Yoshida², Jens Köhler², Atsuko Ogino², Ryu-Suke Nozawa⁸, Shriram K Sundararaman⁹, Tran C Thai², Mizuki Homme¹⁰, Brandon Piel², Sophie Kivlehan¹¹, Bonje N Obua¹¹, Connor Purcell¹², Mamiko Yajima¹³, Thanh U Barbie¹⁴, Patrick H Lizotte¹¹, Pasi A Jänne², Cloud P Paweletz¹¹, Prafulla C Gokhale³, David A Barbie¹⁵

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: shunsuke.kitajima@jfcr.or.jp.
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: david_barbie@dfci.harvard.edu.

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.

Publication types

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

MeSH terms

Decitabine
Genes, ras
Humans
Ligands
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / metabolism

Substances

KRAS protein, human
Ligands
Decitabine
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding