Citations 2
Syk-dependent alternative homologous recombination activation promotes cancer resistance to DNA targeted therapy
Zhou, Qin , Tu, Xinyi , Hou, Xiaonan , Yu, Jia, Zhao, Fei , Huang, Jinzhou , Olson, Anna, Gao, Ming , Luo, Kuntian, Schoolmeester, Kenneth, Weroha, S. John , Wang, Liewei , Mutter, Robert W. , Kloeber, Jake, Zhu, Shouhai , Wu, Zheming , Zeng, Xiangyu , Weroha, John, Mutter, Robert, Lou, Zhenkun , Yu, Jia, Kloeber, Jake A. , Zhang, Yong , Sun, Chenyu , Lou, Zhenkun
No container title available | June 9, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance. We found that Syk is activated by ATM following DNA damage and is recruited to DNA double strand breaks by NBS1. Once at the break site, Syk phosphorylates CtIP, a key mediator of resection and HR, at Thr-847 to promote repair activity, specifically in Syk expressing cancer cells. Syk inhibition or genetic deletion abolished CtIP Thr-847 phosphorylation and overcame the resistant phenotype. Collectively, our findings suggest that Syk drives therapeutic resistance by promoting DNA resection and HR through a novel ATM-Syk-CtIP pathway, and that Syk is a new tumor-specific target to sensitize Syk-expressing tumors to PARPi and other DNA targeted therapy.
MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING
Yang, Qifan, Zeng, Xiangyu , Wang, Manxiang , Tu, Xinyi , Wei, Ting , Xie, Wenzhuan , Guo, Qiang , Kloeber, Jake A. , Cao, Yueyu, Guo, Guijie , Zhou, Qin , Huang, Jinzhou , Zhang, Kai , Luo, Kuntian, Kim, Wootae , Hou, Jing , Shi, Yu , Zhu, Qian , Hu, Sheng , Yue, Junqiu , Pi, Guoliang , Kloeber, Jake A , Liu, Li , Kim, Wootae , Zhu, Qian , Wei, Ting , Zeng, Xiangyu , Zhang, Yong , Dong, Shuang , Yang, Bin , Zhang, Chao , Zhao, Fei Linda , Liu, Li , Wang, Mingwei , Yin, Ping , Deng, Min , Chen, Lifeng , Lou, Zhenkun , Guo, Guijie
Cancer Discovery | June 7, 2021 | Volume: 11 | Issue: 11 | Pages: 2726-2737
Abstract Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3′-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. Significance: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR–tyrosine kinase inhibitor resistant-related MET amplification. This article is highlighted in the In This Issue feature, p. 2659