Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer

Sep 23, 2026

Uploaded by hdkawk

Lack of durable responses to oncogenic Kras inhibition in pancreatic ductal adenocarcinoma highlights the need for effective combinations. This study shows that Kras targeting with MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including Tregs, effector, and exhausted T cells, into the pancreatic tumor microenvironment. Kras inhibition enables priming of PDAC for anti-CTLA4 immune checkpoint therapy, outperforming multiple alternative combination strategies. Mechanistically, anti-CTLA4 reprograms effector Tregs toward a naive phenotype, reverses CD8+ exhaustion, and promotes functional tertiary lymphoid structures. Single-cell ATAC sequencing links Treg reprogramming to epigenetic downregulation of AP-1 family transcription factors in the IL-35 promoter region, revealing a clinically actionable vulnerability.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Key findings

T-cell recruitment after Kras targeting

Anti-CTLA4 synergy versus other combinations

Mechanistic basis of Treg reprogramming and CD8+ restoration

Epigenetic regulation revealed by single-cell ATAC sequencing

Background and rationale

Kras as a therapeutic breakthrough and emerging resistance

Need for microenvironment-dependent vulnerabilities

Article [https://doi.org/10.1038/s41467-026-75960-3](https://doi.org/10.1038/s41467-026-75960-3) Oncogenic Kras targeting with MRTX1133 or Daraxonrasib speciﬁcallysynergize with antiCTLA4 to promote anti-tumor immunity in pancreatic cancer Received: 22 October 2025 | Accepted: 16 July 2026 | | --- | | | | Check for updates | Krishnan K. Mahadevan1, Ana S. Maldonado1, Bingrui Li1, Aaron A. Bickert1, Adrian Kacperczyk-Perdyan1, Shreyasee V. Kumbhar1, Sujan Piya 2, Amari M. Sockwell1, Sami J. Morse1, Kent Arian1, Hikaru Sugimoto1, Shabnam Shalapour 1, David S. Hong 3, Timothy P. Heffernan 4, Anirban Maitra2 & Raghu Kalluri 1,5,6,7 Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell inﬁltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell inﬂux and offers a therapeutic window to speciﬁcally prime PDAC to anti-CTLA4 immune checkpoint blockade efﬁcacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications. Pharmacological targeting of oncogenic Kras (Kras*), a mutation that was considered ‘undruggable’ until recently represents a signiﬁcant breakthrough in the treatment of several malignancies and has the potential to beneﬁt numerous cancer patients. Strategies to inhibit oncogenic Kras include small molecule inhibitors of KrasG12D (MRTX1133, RMC-9805, ASP3082 and KRB-456)1–5 and KrasG12C mutations (Sotorasib/AMG-5106–8, Adagrasib/MRTX8499–11), pan-Ras inhibitors (RMC-6236, RMC-7977)12,13, pan Kras inhibitors (BI-2493, BI- 2865)14, iExosomes inhibiting KrasG12D 15,16 and drugs inhibiting downstream targets of oncogenic Kras such as MEK and ERK17,18. Among the different oncogenic Kras mutations, G12C mutations are frequent in non-small cell lung cancers (NSCLCs) and colorectal cancers, whereas G12D mutations are frequent in PDAC and cholangiocarcinoma19–21. Other frequently mutated Kras genes include G12R and G12V 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. 6Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. 7Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. e-mail: [rkalluri@mdanderson.org](rkalluri@mdanderson.org) mutations in PDAC22. KrasG12D represents the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC)22,23. Targeting KrasG12D with small molecule inhibitors such as MRTX1133, BI-2493, RMC-6236 (Daraxonrasib), and iExosomes resulted in robust increase in survival in mouse models of PDAC1,3,7,10,14–16,24. However, prolonged treatment with small molecule inhibitors of Kras* eventually resulted in development of resistance toKras*

FAQs

Why are combination therapies needed after oncogenic Kras inhibition in pancreatic cancer?

Sustained responses to Kras inhibition are limited in pancreatic ductal adenocarcinoma, and resistance with tumor relapse can emerge. The work focuses on identifying combination strategies that exploit microenvironment-dependent vulnerabilities.

What immune changes occur after Kras targeting with MRTX1133 or Daraxonrasib?

Kras targeting recruits diverse T-cell infiltrates into the PDAC microenvironment, including regulatory T cells (Tregs), effector T cells, and exhausted T cells.

How does the anti-CTLA4 combination improve anti-tumor immunity, mechanistically?

Anti-CTLA4 transcriptionally reprograms effector Tregs toward a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures. Single-cell ATAC sequencing indicates epigenetic control through downregulation of AP-1 family transcription factors in the IL-35 promoter region.

Sep 23, 2026

Uploaded by hdkawk