CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC

Date:	July 11, 2026
PMID:	42436354
Category:	N/A
Authors:	Kathleen M McAndrews, Krishnan K Mahadevan, Bingrui Li, Anaïs M Comptdaer, Amari M Sockwell, Sami J Morse, Patience J Kelly, Sarah I Patel, Michelle L Kirtley, Barbara A Moreno Diaz, Hengyu Lyu, David H Peng, Sima Khazaei, Aislyn Schalck, Xunian Zhou, Hikaru Sugimoto, Aaron A Bickert, Lakshmi Kavitha Sthanam, Meagan R Taylor, Shreyasee V Kumbhar, Kent A Arian, Yasaman Barekatain, Francesca Paradiso, Paola A Guerrero, Vincent Bernard, Navid Sobhani, Alondra N Camacho-Acevedo, Kiara E Bornes, Phuong Thao Tran, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri
Abstract:

Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with about 50% of patients presenting with KRAS^G12D mutations. Small molecule inhibitors targeting KRAS^G12D suppress PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained efficacy of KRAS^G12D inhibition and mechanisms of resistance to KRAS^G12D suppression remain to be elucidated. Here, integrated spatial transcriptomics, single-cell RNA sequencing, and CODEX-based spatial proteomics analyses of PDAC mouse models uncover that while KRAS^G12D inhibition by MRTX1133 initially increases CD11c⁺ cells and T cell infiltration proximal to cancer cells, long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8. CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself or in combination with αCTLA-4 immunotherapy overcomes resistance to KRAS^G12D inhibition. We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RAS^G12D(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center