KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer

Yongkun Wei; Minghui Liu; Er Yen Yen; Jun Yao; Zhenzhen Xun; Phuoc T. Nguyen; Xiaofei Wang; Zecheng Yang; Abdelrahman Yousef; Dean Pan; Yanqing Jin; Ching Fei Li; Madelaine S. Theardy; Jangho Park; Yiming Cai; Mitsunobu Takeda; Matthew Vasquez; Elizabeth M. Park; David H. Peng; Yong Zhou; Hong Zhao; Timothy P. Heffernan; Andrea Viale; Huamin Wang; Stephanie S. Watowich; Han Liang; Dan Zhao; Ronald A. DePinho; Wantong Yao; Haoqiang Ying

doi:10.1158/0008-5472.CAN-25-2024

KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer

Yongkun Wei, Minghui Liu, Er Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T. Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching Fei Li, Madelaine S. Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M. Park, David H. Peng, Yong ZhouHong Zhao, Timothy P. Heffernan, Andrea Viale, Huamin Wang, Stephanie S. Watowich, Han Liang, Dan Zhao, Ronald A. DePinho, Wantong Yao, Haoqiang Ying

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment are therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared with the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathologic and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a "hot" tumor immune microenvironment. Immunoprofiling revealed that CD24, a "do not eat me" signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. SIGNIFICANCE: Generation of an autochthonous KRASG12C-driven pancreatic cancer model enabled elucidation of specific effects of KRASG12C during tumor development, revealing CD24 as an actionable adaptive mechanism in cancer cells induced upon KRASG12C inhibition.

Original language	English (US)
Pages (from-to)	4825-4838
Number of pages	14
Journal	Cancer research
Volume	85
Issue number	23
DOIs	https://doi.org/10.1158/0008-5472.CAN-25-2024
State	Published - Dec 1 2025

Keywords

CD24 Antigen/metabolism
Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors
Pancreatic Neoplasms/pathology
Animals
Mice
Humans
Carcinoma, Pancreatic Ductal/drug therapy
Tumor Microenvironment/immunology
Cell Line, Tumor
Xenograft Model Antitumor Assays
Signal Transduction
Mice, Transgenic
Mutation

ASJC Scopus subject areas

Oncology
Cancer Research

Divisions

Medical Oncology

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10.1158/0008-5472.CAN-25-2024

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Wei, Y., Liu, M., Yen, E. Y., Yao, J., Xun, Z., Nguyen, P. T., Wang, X., Yang, Z., Yousef, A., Pan, D., Jin, Y., Li, C. F., Theardy, M. S., Park, J., Cai, Y., Takeda, M., Vasquez, M., Park, E. M., Peng, D. H., ... Ying, H. (2025). KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer. Cancer research, 85(23), 4825-4838. https://doi.org/10.1158/0008-5472.CAN-25-2024

Wei, Y, Liu, M, Yen, EY, Yao, J, Xun, Z, Nguyen, PT, Wang, X, Yang, Z, Yousef, A, Pan, D, Jin, Y, Li, CF, Theardy, MS, Park, J, Cai, Y, Takeda, M, Vasquez, M, Park, EM, Peng, DH, Zhou, Y, Zhao, H, Heffernan, TP, Viale, A, Wang, H, Watowich, SS, Liang, H, Zhao, D, DePinho, RA, Yao, W & Ying, H 2025, 'KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer', Cancer research, vol. 85, no. 23, pp. 4825-4838. https://doi.org/10.1158/0008-5472.CAN-25-2024

@article{d9c0f10a1d46471995e0346c8c4b4847,

title = "KRAS Inhibition Activates an Actionable CD24 {"}Do Not Eat Me{"} Signal in Pancreatic Cancer",

abstract = "KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment are therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared with the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathologic and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a {"}hot{"} tumor immune microenvironment. Immunoprofiling revealed that CD24, a {"}do not eat me{"} signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. SIGNIFICANCE: Generation of an autochthonous KRASG12C-driven pancreatic cancer model enabled elucidation of specific effects of KRASG12C during tumor development, revealing CD24 as an actionable adaptive mechanism in cancer cells induced upon KRASG12C inhibition.",

keywords = "CD24 Antigen/metabolism, Proto-Oncogene Proteins p21(ras)/antagonists \& inhibitors, Pancreatic Neoplasms/pathology, Animals, Mice, Humans, Carcinoma, Pancreatic Ductal/drug therapy, Tumor Microenvironment/immunology, Cell Line, Tumor, Xenograft Model Antitumor Assays, Signal Transduction, Mice, Transgenic, Mutation",

author = "Yongkun Wei and Minghui Liu and Yen, \{Er Yen\} and Jun Yao and Zhenzhen Xun and Nguyen, \{Phuoc T.\} and Xiaofei Wang and Zecheng Yang and Abdelrahman Yousef and Dean Pan and Yanqing Jin and Li, \{Ching Fei\} and Theardy, \{Madelaine S.\} and Jangho Park and Yiming Cai and Mitsunobu Takeda and Matthew Vasquez and Park, \{Elizabeth M.\} and Peng, \{David H.\} and Yong Zhou and Hong Zhao and Heffernan, \{Timothy P.\} and Andrea Viale and Huamin Wang and Watowich, \{Stephanie S.\} and Han Liang and Dan Zhao and DePinho, \{Ronald A.\} and Wantong Yao and Haoqiang Ying",

note = "Publisher Copyright: {\textcopyright}2025 American Association for Cancer Research.",

year = "2025",

month = dec,

day = "1",

doi = "10.1158/0008-5472.CAN-25-2024",

language = "English (US)",

volume = "85",

pages = "4825--4838",

journal = "Cancer research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "23",

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TY - JOUR

T1 - KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer

AU - Wei, Yongkun

AU - Liu, Minghui

AU - Yen, Er Yen

AU - Yao, Jun

AU - Xun, Zhenzhen

AU - Nguyen, Phuoc T.

AU - Wang, Xiaofei

AU - Yang, Zecheng

AU - Yousef, Abdelrahman

AU - Pan, Dean

AU - Jin, Yanqing

AU - Li, Ching Fei

AU - Theardy, Madelaine S.

AU - Park, Jangho

AU - Cai, Yiming

AU - Takeda, Mitsunobu

AU - Vasquez, Matthew

AU - Park, Elizabeth M.

AU - Peng, David H.

AU - Zhou, Yong

AU - Zhao, Hong

AU - Heffernan, Timothy P.

AU - Viale, Andrea

AU - Wang, Huamin

AU - Watowich, Stephanie S.

AU - Liang, Han

AU - Zhao, Dan

AU - DePinho, Ronald A.

AU - Yao, Wantong

AU - Ying, Haoqiang

PY - 2025/12/1

Y1 - 2025/12/1

N2 - KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment are therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared with the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathologic and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a "hot" tumor immune microenvironment. Immunoprofiling revealed that CD24, a "do not eat me" signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. SIGNIFICANCE: Generation of an autochthonous KRASG12C-driven pancreatic cancer model enabled elucidation of specific effects of KRASG12C during tumor development, revealing CD24 as an actionable adaptive mechanism in cancer cells induced upon KRASG12C inhibition.

AB - KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment are therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared with the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathologic and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a "hot" tumor immune microenvironment. Immunoprofiling revealed that CD24, a "do not eat me" signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. SIGNIFICANCE: Generation of an autochthonous KRASG12C-driven pancreatic cancer model enabled elucidation of specific effects of KRASG12C during tumor development, revealing CD24 as an actionable adaptive mechanism in cancer cells induced upon KRASG12C inhibition.

KW - CD24 Antigen/metabolism

KW - Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors

KW - Pancreatic Neoplasms/pathology

KW - Animals

KW - Mice

KW - Humans

KW - Carcinoma, Pancreatic Ductal/drug therapy

KW - Tumor Microenvironment/immunology

KW - Cell Line, Tumor

KW - Xenograft Model Antitumor Assays

KW - Signal Transduction

KW - Mice, Transgenic

KW - Mutation

UR - https://www.scopus.com/pages/publications/105023544399

UR - https://www.scopus.com/inward/citedby.url?scp=105023544399&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-25-2024

DO - 10.1158/0008-5472.CAN-25-2024

M3 - Article

C2 - 40966362

AN - SCOPUS:105023544399

SN - 0008-5472

VL - 85

SP - 4825

EP - 4838

JO - Cancer research

JF - Cancer research

IS - 23

ER -

KRAS Inhibition Activates an Actionable CD24 "Do Not Eat Me" Signal in Pancreatic Cancer

Abstract

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