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Cited by 107Cancer Immunotherapy and Biomarkersinterferon and immune responsesLung Cancer Treatments and Mutations

MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

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Kitajima, Shunsuke, Tani, Tetsuo, Springer, Benjamin F., Campisi, Marco, Osaki, Tatsuya, Haratani, Koji, Chen, Minyue, Knelson, Erik H. +20 more·2022·Cancer Cell
DOI 10.1016/j.ccell.2022.08.015PMC PMC9561026
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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.

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Crossref · 10.1016/j.ccell.2022.08.015

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  • STING is silenced in STK11-deficient tumors, which contributes to their low immunogenicity.

    “For example, it has been observed that STING is silenced in STK11-deficient tumors, which contributes to their low immunogenicity (12, 13).”

    From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [13]

    The Introduction reports that STING is silenced in KRAS-LKB1–mutated lung cancer cells and links loss of tumor-cell STING signaling to reduced cytotoxic T-cell infiltration. The claim extends this finding to STK11-deficient tumors generally; the Discussion says KRAS-wild-type LKB1-mutated tumors appear less reliant on this biology. Page numbers were not available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Studies have shown that STK11 loss-of-function mutations result in epigenetic changes that lead to silencing of immune genes.

    “Indeed, studies have shown that STK11 loss-of-function mutations result in epigenetic changes that lead to silencing of immune genes (3, 13).”

    From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [13]

    The Introduction reports epigenetic silencing of the immune-signaling gene STING in KRAS-LKB1-mutant lung cancer cells, and the Discussion describes methylation mechanisms involved in that silencing (page numbers unavailable). This supports the claim in that specific setting, but not its broader implication that STK11 loss-of-function alone leads to silencing of immune genes generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Kitajima, S., Tani, T., Springer, B. F., Campisi, M., Osaki, T., Haratani, K., Chen, M., Knelson, E. H., Mahadevan, N. R., Ritter, J., Yoshida, R., Köhler, J., Ogino, A., Nozawa, R.-S., Sundararaman, S. K., Thai, T. C., Homme, M., Piel, B., Kivlehan, S., Obua, B. N., Purcell, C., Yajima, M., Barbie, T. U., Lizotte, P. H., Jänne, P. A., Paweletz, C. P., Gokhale, P. C., & Barbie, D. A.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • Institute of Industrial Science, The University of Tokyo (JP)
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
  • Dana-Farber Brigham Cancer Center (US)
  • Japanese Foundation For Cancer Research (JP)
  • Beth Israel Deaconess Medical Center (US)
  • Brown University (US)
Corresponding author
  • Kitajima, Shunsuke
  • Barbie, David A.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2022-10
Volume
40
Issue
10
Pages
1128-1144.e8
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2022.08.015
PMC
PMC9561026
OpenAlex
W4296663392
Cited by
107
References
14
Citations by year
2026: 22 · 2025: 31 · 2024: 29 · 2023: 21 · 2022: 4
FWCI
8.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Eli Lilly and Company
  • Dana-Farber/Harvard Cancer Center
  • Lilly Oncology
  • AstraZeneca
  • Boehringer Ingelheim
  • Expect Miracles Foundation
  • Merck
  • Uehara Memorial Foundation
  • Novartis
  • Foghorn Therapeutics
  • Takeda Pharmaceuticals U.S.A.
  • Ludwig Center at Harvard
  • National Cancer Institute (NsluIH 5 P30 CA06516)
  • Dana-Farber Cancer Institute
  • Revolution Medicines
  • AbbVie
  • Takeda Oncology
  • Array BioPharma
  • Northeastern University
  • Takeda Science Foundation
  • National Institutes of Health (R01CA190294)
  • Canadian Asian Studies Association
  • Janssen Pharmaceuticals
  • Japan Society for the Promotion of Science (20H03521)
  • EMD Serono
  • Japan Agency for Medical Research and Development (20cm0106705h0001, 21cm0106705h0002)
  • Associazione Italiana per la Ricerca sul Cancro
  • Gilead Sciences
  • Robert A. and Renee E. Belfer Family Foundation
  • Princess Takamatsu Cancer Research Fund
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
STING, 2'-3'-cGAMP, mitochondrial dysfunction, T-cell exclusion, micronuclei, decitabine, epigenetic reprogramming, STAT1, immunogenicity, combination therapy
MeSH terms
Decitabine, Humans, Ligands, Lung Neoplasms, Genes, ras, Proto-Oncogene Proteins p21(ras)

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