CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
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Research Article Cell biology Oncology

CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models

Abstract

Inactivation of cyclin-dependent kinase 12 (CDK12) defines an immunogenic molecular subtype of prostate cancer characterized by genomic instability and increased intratumoral T cell infiltration. This study revealed that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis showed that reduced CDK12/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12/13 depletion or targeted degradation induced cytosolic nucleic acid release, triggering STING pathway activation. CDK12/13 degradation delayed tumor growth and synergized with anti–PD-1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8+ T cell infiltration and activation within tumors. Notably, the antitumor effects of this combination required STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12-mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate antitumor immunity and potentiate responses to immunotherapies.

Authors

Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan

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CDK12/13 inactivation activates antitumor immunity and enhances response to ICB.

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CDK12/13 inactivation activates antitumor immunity and enhances response...
(A) Growth curves of subcutaneous (s.c.) tumors derived from Myc-CaP cells with or without Cdk12, Cdk13, or Cdk12/13 depletion in FVB mice (n = 4–5 mice per group) treated with IgG or anti–PD-1 (α-PD-1). (B) Growth curves of s.c. tumors derived from the Cdk12KO-sgp53 tumor cells in C57BL/6 mice (n = 5–6 mice per group) treated with vehicle, α-PD-1, YJ1206, or the combination of α-PD-1 and YJ1206 (combo). (C) Growth curves of s.c. tumors derived from Myc-CaP cells in FVB mice (n = 5–6 mice per group) treated with vehicle, α-PD-1, cGAMP, or the combination of α-PD-1 and cGAMP (combo). Intratumoral injections were performed for cGAMP administration. (D and E) Growth curves of s.c. tumors derived from the specified tumor cells in the indicated mice (n = 5–10 mice per group) treated with vehicle, α-PD-1, YJ1206, or the combination of α-PD-1 and YJ1206 (combo). (F) Assessment by CombPDX for synergism of α-PD-1 and YJ1206 in the indicated models treated in B, D, and E. (G) Body weight of the indicated mice after treatment by the indicated agents. YJ1206 was administered orally at a dose of 100 mg/kg, 3 times per week, and α-PD-1 was administered intraperitoneally at a dose of 200 μg/mouse every 3 days. Data are displayed as mean ± SEM in A–E and as mean ± SD in G. Significance in B–E was determined by 2-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Bonferroni’s correction was applied for multiple comparisons.