The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy
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Abstract
KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non–small cell lung cancer (NSCLC). PD-1 inhibitors are approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) are needed. KRASG12C mutations are smoking-associated transversion mutations associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive tumor microenvironment. To evaluate the potential of MRTX849 to augment CIT, its impact on immune signaling and response to CIT was evaluated. In human tumor xenograft models, MRTX849 increased MHC class I protein expression and decreased RNA and/or plasma protein levels of immunosuppressive factors. In a KrasG12C-mutant CT26 syngeneic mouse model, MRTX849 decreased intratumoral myeloid-derived suppressor cells and increased M1-polarized macrophages, dendritic cells, CD4+, and CD8+ T cells. Similar results were observed in lung KrasG12C-mutant syngeneic and a genetically engineered mouse (GEM) model. In the CT26 KrasG12C model, MRTX849 demonstrated marked tumor regression when tumors were established in immune-competent BALB/c mice; however, the effect was diminished when tumors were grown in T-cell–deficient nu/nu mice. Tumors progressed following anti–PD-1 or MRTX849 single-agent treatment in immune-competent mice; however, combination treatment demonstrated durable, complete responses (CRs). Tumors did not reestablish in the same mice that exhibited durable CRs when rechallenged with tumor cell inoculum, demonstrating these mice developed adaptive antitumor immunity. In a GEM model, treatment with MRTX849 plus anti–PD-1 led to increased progression-free survival compared with either single agent alone. These data demonstrate KRAS inhibition reverses an immunosuppressive tumor microenvironment and sensitizes tumors to CIT through multiple mechanisms.
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In syngeneic mouse models, adagrasib depleted intratumoural MDSCs and increased cytotoxic immune cell infiltration; tumour responses occurred in immunocompetent BALB/c mice but were attenuated in T cell-deficient mice.
“Moreover, adagrasib depleted intratumoural MDSCs while increasing cytotoxic immune cell infiltration in syngeneic mouse models; tumour responses were observed in these immunocompetent BALB/c mice, but were attenuated in T cell-deficient mice162.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [162]
Combining adagrasib with an anti-PD-1 antibody produced durable antitumour responses in mice, with evidence of immunological memory.
“Furthermore, combination treatment with adagrasib and an anti-PD-1 antibody resulted in durable antitumour responses, again, with evidence of immunological memory responses162.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [162]
Adagrasib induces MHC class I expression and a pro-inflammatory state in human KRASG12C-mutant tumour cell xenografts.
“Briere et al.162 demonstrated that adagrasib induces MHC class I (MHC I) expression and promotes a pro-inflammatory state in human KRASG12C-mutant tumour cell xenografts.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [162]
Preclinical studies suggest sotorasib and adagrasib can induce a more proinflammatory and TIL-infiltrated TME in mouse models, leading to durable complete responses with anti-PD-1 therapy.
“Preclinical studies suggest that sotorasib and adagrasib can induce a more proinflammatory and TIL-infiltrated TME in mouse models, translating into durable complete responses in combination with anti-PD-1 therapy (21, 74).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [74]
KRAS G12C inhibitors sotorasib and adagrasib promote a pro-inflammatory microenvironment in murine models by increasing CD8+ T-cell infiltration and decreasing immunosuppressive cells.
“KRAS G12C inhibitors sotorasib and adagrasib have shown to promote a pro-inflammatory microenvironment in murine models by increasing CD8 + T-cell infiltration and by decreasing immunosuppressive cells such as MDSCs, M2-polarized macrophages, Tregs and potentiate anti-PD1 antibody therapy [71, 161].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [161]
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- Authors
- Briere, D. M., Li, S., Calinisan, A., Sudhakar, N., Aranda, R., Hargis, L., Peng, D. H., Deng, J., Engstrom, L. D., Hallin, J., Gatto, S., Fernandez-Banet, J., Pavlicek, A., Wong, K.-K., Christensen, J. G., & Olson, P.
- Affiliations
- Mirati Therapeutics (United States) (US)
- NYU Langone Health (US)
- 3Monoceros Biosystems LLC, San Diego, California.
- Corresponding author
- Olson, Peter
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2021-03-15
- Volume
- 20
- Issue
- 6
- Pages
- 975-985
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC8444277
- OpenAlex
- W3136047951
- Cited by
- 168
- References
- 36
- Citations by year
- 2026: 20 · 2025: 37 · 2024: 33 · 2023: 28 · 2022: 37 · 2021: 13
- FWCI
- 10.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- N/A
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- adagrasib, KRAS-mutant non-small cell lung cancer, tumor immune microenvironment, anti-PD-1 combination therapy, MHC class I expression, myeloid-derived suppressor cells, M1 macrophages, tumor-infiltrating T cells, tumor rechallenge, genetically engineered mouse models
- MeSH terms
- Immune Checkpoint Inhibitors, Acetonitriles, Animals, Antineoplastic Agents, Disease Models, Animal, Humans, Piperazines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Cell Proliferation, Mice, Tumor Microenvironment
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