Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRASG12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides insights into the effect of KRASG12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS-mutant cancers.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-12-24
DOI
https://doi.org/10.1172/jci174249
Citations
13
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
3.04
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article

Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models

Alison Chafitz, Fei Li, Alice H. Berger, Christina C. Kuismi et al.
13 citations
Journal of Clinical Investigation
Protein Degradation and Inhibitors
3.04
article

Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models

Alison Chafitz, Fei Li, Alice H. Berger, Christina C. Kuismi, Fiona Sherman, Jiajia Gu, Nathanael S. Gray, Shengqing Gu, Saurav Kumar, Cassandra Thakurdin, Behnam Nabet, Magdalena A. Ploszaj, Annabel T. Olson, Mary Meynardie, Michela Ranieri, Tullia C. Bruno, Joy Chen, Benjamin A. Nacev, Hu Baoli, Janaye Stephens, Xuejiao Sun, Kwok-Kin Wong, Jaylen M. Powell, Ke Geng, Hye Mi Kim, Jing Li, Wei Chen, Yang Liu, Hua Zhang, Ting Chen, Dezhi Li, Yiting Li, Daniel Levin, Xuerui Wang, Han Han, Ze-Yan Zhang, Yuanwang Pan, Hao Yuan, Tinghu Zhang, Xiaoyang Zhang, Medard Ernest Kaiza, Asia M. Williams, Mia S. Donald-Paladino
article en
13 citations

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRASG12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides insights into the effect of KRASG12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS-mutant cancers.

Journal of Clinical InvestigationVol. 135(2)
Shanghai Medical College of Fudan University (CN), The University of Texas MD Anderson Cancer Center (US), University of Illinois Urbana-Champaign (US), University of Pittsburgh (US), University of Washington (US), University of Utah (US), Fudan University (CN), Huntsman Cancer Institute (US), Office of Science (US), NYU Langone Health (US), Fred Hutch Cancer Center (US), UPMC Hillman Cancer Center (US), Children's Hospital of Pittsburgh (US), University of Pittsburgh Medical Center (US), Neurological Surgery (US), Office of Basic Energy Sciences (US), New York University (US), Stanford University (US), Tsinghua University (CN)
Good health and well-being
Openalex Percentile: Top 8%
Protein Degradation and Inhibitors
3.04
DOIOpen Access PDFOpenAlex
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