MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer PMID: 36150391

ADC Targets in Oncology

2026-04-10

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].

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.