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  2. JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers

JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers

  • Cancer Lett. 2023 Dec 13:216517. doi: 10.1016/j.canlet.2023.216517.
Xuxiu Lu 1 Rilei Yu 1 Zhen Li 2 Mengke Yang 2 Jiajia Dai 3 Ming Liu 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
  • 2 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 3 Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China.
  • 4 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: lmouc@ouc.edu.cn.
Abstract

Src homology 2 domain-containing Phosphatase (SHP2) is a non-receptor protein Phosphatase that transduces signals from upstream Receptor Tyrosine Kinases (RTKs)/non-RTKs to Ras/MAPK pathway. Accumulating studies indicated that SHP2 is a critical mediator of resistance to current targeted therapies in multiple cancers. Here, we reported a novel SHP2 allosteric inhibitor JC-010a, which was highly selective to SHP2 and bound at the "tunnel" allosteric site of SHP2. The effect of JC-010a on combating RTK/non-RTK or MAPK inhibitors-induced acquired resistance was explored. Our study demonstrated that JC-010a monotherapy significantly inhibited the proliferation of Cancer cells with different oncogenic drivers via inhibiting signaling through SHP2. Importantly, JC-010a abolished acquired resistance induced by targeted therapies: in KRAS-mutant cancers, JC-010a abrogated selumetinib-induced adaptive resistance mediated by RTK/SHP2; in BCR-ABL-driven leukemia cells, we demonstrated JC-010a inhibited Bcr-Abl T315I mutation-mediated imatinib resistance and proposed a novel mechanism of JC-010a involving the disrupted co-interaction of SHP2, Bcr-Abl, and Hsp90; in non-small cell lung Cancer (NSCLC) cells, JC-010a inhibited both EGFR T790M/C797S mutation and alternate RTK-driven resistance to gefitinib or osimertinib; importantly, we first proposed a novel potential therapeutic strategy for RET-rearranged Cancer, we confirmed that JC-010a monotherapy inhibited cell resistance to BLU-667, and JC-010a/BLU-667 combination prolonged Anticancer response both in vivo and in vitro Cancer models by inhibiting the alternate MET activation-induced Ras/MAPK reactivation, thereby promoting Cancer cell Apoptosis. These findings suggested that JC-010a was a novel selective SHP2 allosteric inhibitor, and combing JC-010a with current targeted therapy agents provided a promising therapeutic approach for clinical resistant cancers.

Keywords

Acquired resistance; Cancer; JC-010a; NSCLC; SHP2.

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