SHP2 inhibition enhances the effects of tyrosine kinase inhibitors in preclinical models of treatment-naïve ALK-, ROS1-, or EGFR-altered non-small-cell lung cancer

After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. Here we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non-small-cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo. Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC. READ ARTICLE

Molecular Cancer Therapeutics DOI: 10.1158/1535-7163.MCT-20-0965

Authors: Hirohisa Kano, Eiki Ichihara, Hiromi Watanabe, Kazuya Nishii, Chihiro Ando, Takamasa Nakasuka, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda and Katsuyuki Kiura

Pre-Clinical, group5Kirk SmithJune 22, 2021ALK, ROS1, EGFR, SHP2, NSCLC, ERK

Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies

Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure–activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties. READ ARTICLE

Acta Pharmaceutica Sinica B DOI: 10.1016/j.apsb.2020.07.010

Authors: Zhendong Song, Meijing Wang, Yang Ge, Xue-Ping Chen, Ziyang Xu, Yang Sun, Xiao-Feng Xiong

Review PaperKirk SmithJuly 15, 2020SHP2, Phosphatase, Selectivity, Allosteric inhibitor, Tumor therapy

SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib—a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK—and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance. READ ARTICLE

Nature Medicine DOI: 10.1038/nm.4497

Authors: Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman