Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model

Authors

Yonghong Liu
Jincheng Han
Wen-Hao Hsu
Kyle A LaBella
Pingna Deng
Xiaoying Shang
Paulino Tallón de Lara
Li Cai
Shan Jiang
Ronald A DePinho

Language

English

Publication Date

1-13-2025

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-24-0489

PMID

39348506

PMCID

PMC11858029

PubMedCentral® Posted Date

7-13-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.

Keywords

Proto-Oncogene Proteins p21(ras), Animals, Mice, Humans, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Tumor Microenvironment, Disease Models, Animal, Immunotherapy, Pancreatic cancer, Combination immunotherapy, KRAS

Published Open-Access

yes

Recommended Citation

Liu, Yonghong; Han, Jincheng; Hsu, Wen-Hao; et al., "Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model" (2025). Faculty, Staff and Student Publications. 5532.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5532