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

  • EMBO J. 2026 Aug;45(16):5727-5758. doi: 10.1038/s44318-026-00854-5.
Kathleen M McAndrews  1 ,  Krishnan K Mahadevan  1 ,  Bingrui Li  1 ,  Anaïs M Comptdaer  1 ,  Amari M Sockwell  1 ,  Sami J Morse  1 ,  Patience J Kelly  1 ,  Sarah I Patel  1 ,  Michelle L Kirtley  1 ,  Barbara A Moreno Diaz  1 ,  Hengyu Lyu  2 ,  David H Peng  2 ,  Sima Khazaei  2 ,  Aislyn Schalck  2 ,  Xunian Zhou  1 ,  Hikaru Sugimoto  1 ,  Aaron A Bickert  1 ,  Lakshmi Kavitha Sthanam  1 ,  Meagan R Taylor  1 ,  Shreyasee V Kumbhar  1 ,  Kent A Arian  1 ,  Yasaman Barekatain  1 ,  Francesca Paradiso  3 ,  Paola A Guerrero  3 ,  Vincent Bernard  4 ,  Navid Sobhani  1 ,  Alondra N Camacho-Acevedo  1 ,  Kiara E Bornes  1 ,  Phuong Thao Tran  1 ,  Anirban Maitra  3  5 ,  Timothy P Heffernan  2 ,  Raghu Kalluri  6  7  8  9
Affiliations
  • 1. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 7. Department of Bioengineering, Rice University, Houston, TX, USA. [email protected].
  • 8. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 9. Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. [email protected].
PMID: 42436354 DOI: 10.1038/s44318-026-00854-5
Abstract

Mutations in KRAS are a dominant driver of Pancreatic Ductal Adenocarcinoma (PDAC), with about 50% of patients presenting with KRASG12D mutations. Small molecule inhibitors targeting KRASG12D suppress PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D 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 KRASG12D 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 KRASG12D inhibition. We also provide evidence of CDK8 upregulation in PDX Tumors resistant to inhibitors selective for Ras(ON) and RasG12D(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance.

Products