Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
8 affiliations
- 1Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 2Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 3Department of Investigative Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 4Insititute for Applied Science and TRACTION platform, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 5Department of Bioengineering, Rice University, Houston, TX, USA. [email protected]
- 6Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected]
- 7Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected]
- 8Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. [email protected]
Abstract
Lack of sustained response to oncogenic Kras (Kras*) inhibition in preclinical models and patients with pancreatic ductal adenocarcinoma (PDAC) emphasizes the need to identify impactful synergistic combination therapies to achieve robust clinical benefit. Kras* targeting results in an influx of T cell infiltrates including Tregs, effector CD8 + T cells and exhausted CD8 + T cells expressing several immune checkpoint molecules in PDAC. Here, we probe whether the T cell influx induced by different Kras* inhibitors enable a therapeutic window to prime adaptive immune response in PDAC. Here we report a specific synergy between Kras G12D allele specific inhibitor, MRTX1133 or multi-selective pan-RAS inhibitor, RMC-6236 and anti-CTLA4 immune checkpoint blockade. In contrast, attempted therapeutic combination with multiple other immune checkpoint inhibitors, including anti-PD1, anti-Tim3, anti-Lag3, anti-Vista and anti-4-1BB agonist antibody failed due to compensatory mechanisms mediated by other checkpoints on exhausted CD8 + T cells. Specifically, anti-CTLA4 therapy in Kras* targeted PDAC transcriptionally reprograms effector T regs to a naïve phenotype, reverses CD8 + T cell exhaustion and is associated with recruitment of tertiary lymphoid structures (TLS) containing follicular B cells, interferon (IFN)- stimulated/ activated B cells, plasma cells and germinal center B cells to functionally enable efficacy of immunotherapy with long-term survival. In this regard, inhibition of the TLS with lymphotoxin-β inhibitor (LTBi) or direct B cell depletion reversed the survival benefit conferred by the combination therapy and highlights the function of TLS in generating productive anti-tumor immune responses. Further, single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with relevant clinical implications.
Related
- Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer
- Efficacy and Safety of Daraxonrasib (RMC-6236) in Previously Treated Metastatic RAS-Mutated Pancreatic Ductal Adenocarcinoma: A Systematic Review.
- Cost-Effectiveness of Daraxonrasib vs Chemotherapy in Previously Treated Metastatic Pancreatic Adenocarcinoma
- Lipid and Carbohydrate Modifications Enhance Potency of Antisense Oligonucleotides Targeting Oncogenic KRAS
- Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer
BibTeX
@article{mahadevan2026oncogenic,
title = {{Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer}},
author = {Krishnan K. Mahadevan and Ana S. Maldonado and Bingrui Li and Aaron A. Bickert and Adrian Perdyan and Shreyasee V. Kumbhar and Sujan Piya and Amari M. Sockwell and Sami J. Morse and Kent A. Arian and Hikaru Sugimoto and Shabnam Shalapour and David S. Hong and Timothy Paul Heffernan and Anirban Maitra and Raghu Kalluri},
journal = {Nature Communications},
year = {2026},
month = jul,
doi = {10.1038/s41467-026-75960-3},
url = {https://doi.org/10.1038/s41467-026-75960-3},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
AU - Krishnan K. Mahadevan
AU - Ana S. Maldonado
AU - Bingrui Li
AU - Aaron A. Bickert
AU - Adrian Perdyan
AU - Shreyasee V. Kumbhar
AU - Sujan Piya
AU - Amari M. Sockwell
AU - Sami J. Morse
AU - Kent A. Arian
AU - Hikaru Sugimoto
AU - Shabnam Shalapour
AU - David S. Hong
AU - Timothy Paul Heffernan
AU - Anirban Maitra
AU - Raghu Kalluri
PY - 2026
DA - 2026/07/27
JO - Nature Communications
DO - 10.1038/s41467-026-75960-3
UR - https://doi.org/10.1038/s41467-026-75960-3
AB - Lack of sustained response to oncogenic Kras (Kras*) inhibition in preclinical models and patients with pancreatic ductal adenocarcinoma (PDAC) emphasizes the need to identify impactful synergistic combination therapies to achieve robust clinical benefit. Kras* targeting results in an influx of T cell infiltrates including Tregs, effector CD8 + T cells and exhausted CD8 + T cells expressing several immune checkpoint molecules in PDAC. Here, we probe whether the T cell influx induced by different Kras* inhibitors enable a therapeutic window to prime adaptive immune response in PDAC. Here we report a specific synergy between Kras G12D allele specific inhibitor, MRTX1133 or multi-selective pan-RAS inhibitor, RMC-6236 and anti-CTLA4 immune checkpoint blockade. In contrast, attempted therapeutic combination with multiple other immune checkpoint inhibitors, including anti-PD1, anti-Tim3, anti-Lag3, anti-Vista and anti-4-1BB agonist antibody failed due to compensatory mechanisms mediated by other checkpoints on exhausted CD8 + T cells. Specifically, anti-CTLA4 therapy in Kras* targeted PDAC transcriptionally reprograms effector T regs to a naïve phenotype, reverses CD8 + T cell exhaustion and is associated with recruitment of tertiary lymphoid structures (TLS) containing follicular B cells, interferon (IFN)- stimulated/ activated B cells, plasma cells and germinal center B cells to functionally enable efficacy of immunotherapy with long-term survival. In this regard, inhibition of the TLS with lymphotoxin-β inhibitor (LTBi) or direct B cell depletion reversed the survival benefit conferred by the combination therapy and highlights the function of TLS in generating productive anti-tumor immune responses. Further, single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with relevant clinical implications.
SN - 2041-1723
ER -