Abstract 2084: Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers
Authors: Acker Michael G. , Chen Ying-Nan P. , LaMarche Matthew J. , Chan Ho Man , Fekkes Peter , Garcia-Fortanet Jorge , LaRochelle Jonathan R. , Antonakos Brandon , Chen Christine Hiu-Tung , Chen Zhuoliang , Cooke Vesselina G. , Dobson Jason R. , Deng Zhan , Feng Fei , Firestone Brant , Fodor Michelle , Fridrich Cary , Gao Hui , Hao Huai-Xiang , Jacob Jaison , Ho Samuel , Hsiao Kathy , Kang Zhao B. , Karki Rajesh , Kato Mitsunori , Larrow Jay , Bonte Laura R. La , Liu Gang , Liu Shumei , Majumdar Dyuti , Meyer Matthew J. , Palermo Mark , Pu Minying , Price Edmund , Shakya Subarna , Shultz Michael D. , Venkatesan Kavitha , Wang Ping , Warmuth Markus , Williams Sarah , Yang Guizhi , Yuan Jing , Zhang Ji-Hu , Zhu Ping , Blacklow Stephen C. , Ramsey Timothy , Keen Nicholas J. , Sellers William R. , Stams Travis , Fortin Pascal D. 
Published: July 2017

The non-receptor protein tyrosine phosphatase (PTP) SHP2 is an important component of RTK signaling in response to growth factor stimulus and sits just upstream of the RAS-MAPK signaling cascade. The first oncogenic phosphatase to be identified, SHP2 is dysregulated in multiple human diseases including the developmental disorders Noonan and Leopard syndromes, as well as leukemia, lung cancer and neuroblastoma where aberrant activity of SHP2 leads to uncontrolled MAPK signaling. Cancer-associated activating mutations in SHP2 impart an “auto-on” state of the enzyme, boosting basal activity by shifting the equilibrium away from the auto-inhibited state. Reduction of SHP2 activity through genetic knockdown suppresses tumor growth, validating SHP2 as a target for cancer therapy. SHP099, a recently reported potent and selective allosteric inhibitor of SHP2, stabilizes the auto-inhibited form of SHP2 through interactions with the N-terminal SH2 and C-terminal PTP domains of the protein. SHP099 suppresses MAPK signaling in RTK amplified cancers resulting in suppressed proliferation in vitro and inhibition of tumor growth in mouse tumor xenograft models. Together, these data demonstrate the therapeutic potential of SHP2 inhibition in the treatment of cancer and other RAS/MAPK-linked diseases.

Citation Format: Michael G. Acker, Ying-Nan P. Chen, Matthew J. LaMarche, Ho Man Chan, Peter Fekkes, Jorge Garcia-Fortanet, Jonathan R. LaRochelle, Brandon Antonakos, Christine Hiu-Tung Chen, Zhuoliang Chen, Vesselina G. Cooke, Jason R. Dobson, Zhan Deng, Fei Feng, Brant Firestone, Michelle Fodor, Cary Fridrich, Hui Gao, Huai-Xiang Hao, Jaison Jacob, Samuel Ho, Kathy Hsiao, Zhao B. Kang, Rajesh Karki, Mitsunori Kato, Jay Larrow, Laura R. La Bonte, Gang Liu, Shumei Liu, Dyuti Majumdar, Matthew J. Meyer, Mark Palermo, Minying Pu, Edmund Price, Subarna Shakya, Michael D. Shultz, Kavitha Venkatesan, Ping Wang, Markus Warmuth, Sarah Williams, Guizhi Yang, Jing Yuan, Ji-Hu Zhang, Ping Zhu, Stephen C. Blacklow, Timothy Ramsey, Nicholas J. Keen, William R. Sellers, Travis Stams, Pascal D. Fortin. Conformational activation and allosteric inhibition of SHP2 in RTK-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2084. doi:10.1158/1538-7445.AM2017-2084