CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC
9 affiliations
- 1Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 2TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 3Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 4Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 5Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 6Department of Bioengineering, Rice University, Houston, TX, USA. [email protected]
- 7Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected]
- 8Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected]
- 9Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. [email protected]
Abstract
Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 40% of PDAC patients presenting with KRAS G12D mutations. The recent development of small molecule inhibitors targeting KRAS G12D has enabled targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained therapeutic efficacy of KRAS G12D inhibition and mechanism/s of resistance to KRAS G12D suppression remain to be elucidated. Here, we employed spatial transcriptomics, single cell RNA sequencing, and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRAS G12D inhibition with MRTX1133. While KRAS G12D inhibition initially increases CD11c + cells with impactful T cell infiltration within proximity to cancer cells, long-term treatment with MRTX1133 resulted in reversal of the immune responses leading to KRAS G12D therapy resistance promoted by CDK8, a multiprotein mediator complex associated kinase. CDK8 imparts resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself and in combination with αCTLA-4 immunotherapy overcomes resistance to KRAS G12D inhibition with prolonged survival with translational implications.
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BibTeX
@article{mcandrews2026cdk8,
title = {{CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC}},
author = {Kathleen M. McAndrews and Krishnan K. Mahadevan and Bingrui Li and Anaïs M Comptdaer and Amari M. Sockwell and Sami J. Morse and Patience J. Kelly and Sarah I. Patel and Michelle L. Kirtley and Barbara A. Moreno Diaz and Hengyu Lyu and David H. Peng and Sima Khazaei and Aislyn P. Schalck and Xunian Zhou and Hikaru Sugimoto and Aaron A. Bickert and Lakshmi Kavitha Sthanam and M P H Sarah Taylor and Shreyasee V. Kumbhar and Kent A. Arian and Yasaman Barekatain and Francesca Paradiso and Paola A. Guerrero and Vincent Bernard and Navid Sobhani and Alondra N Camacho-Acevedo and Kiara E. Bornes and Phương Thảo Trần and Anirban Maitra and Timothy Paul Heffernan and Raghu Kalluri},
journal = {The EMBO Journal},
year = {2026},
month = jul,
doi = {10.1038/s44318-026-00854-5},
url = {https://doi.org/10.1038/s44318-026-00854-5},
note = {CC BY},
}
RIS
TY - JOUR
TI - CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC
AU - Kathleen M. McAndrews
AU - Krishnan K. Mahadevan
AU - Bingrui Li
AU - Anaïs M Comptdaer
AU - Amari M. Sockwell
AU - Sami J. Morse
AU - Patience J. Kelly
AU - Sarah I. Patel
AU - Michelle L. Kirtley
AU - Barbara A. Moreno Diaz
AU - Hengyu Lyu
AU - David H. Peng
AU - Sima Khazaei
AU - Aislyn P. Schalck
AU - Xunian Zhou
AU - Hikaru Sugimoto
AU - Aaron A. Bickert
AU - Lakshmi Kavitha Sthanam
AU - M P H Sarah Taylor
AU - Shreyasee V. Kumbhar
AU - Kent A. Arian
AU - Yasaman Barekatain
AU - Francesca Paradiso
AU - Paola A. Guerrero
AU - Vincent Bernard
AU - Navid Sobhani
AU - Alondra N Camacho-Acevedo
AU - Kiara E. Bornes
AU - Phương Thảo Trần
AU - Anirban Maitra
AU - Timothy Paul Heffernan
AU - Raghu Kalluri
PY - 2026
DA - 2026/07/11
JO - The EMBO Journal
DO - 10.1038/s44318-026-00854-5
UR - https://doi.org/10.1038/s44318-026-00854-5
AB - Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 40% of PDAC patients presenting with KRAS G12D mutations. The recent development of small molecule inhibitors targeting KRAS G12D has enabled targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained therapeutic efficacy of KRAS G12D inhibition and mechanism/s of resistance to KRAS G12D suppression remain to be elucidated. Here, we employed spatial transcriptomics, single cell RNA sequencing, and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRAS G12D inhibition with MRTX1133. While KRAS G12D inhibition initially increases CD11c + cells with impactful T cell infiltration within proximity to cancer cells, long-term treatment with MRTX1133 resulted in reversal of the immune responses leading to KRAS G12D therapy resistance promoted by CDK8, a multiprotein mediator complex associated kinase. CDK8 imparts resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself and in combination with αCTLA-4 immunotherapy overcomes resistance to KRAS G12D inhibition with prolonged survival with translational implications.
SN - 0261-4189
SN - 1460-2075
ER -