1. Diverse Mechanisms of Resistance against Osimertinib, a Third-Generation EGFR-TKI, in Lung Adenocarcinoma Cells with an EGFR-Activating Mutation
Fumihiro Ishikawa, Yasunari Kishino, Sojiro Kusumoto, Junji Tsurutani, Koichi Ando, Shigetoshi Nishihara, Hitoshi Yoshida, Yuki Hasebe, Toshimitsu Yamaoka, Ryo Manabe, Hironori Sagara, Tohru Ohmori Cells . 2022 Jul 14;11(14):2201. doi: 10.3390/cells11142201.
Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used as a first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms underlying its anticancer activity, particularly the subsequent development of acquired resistance, are unclear. Herein, we investigated the mechanisms underlying the development of osimertinib resistance by treating NSCLC PC-9 cells (harboring an EGFR-activating mutation) with osimertinib, thereby developing five resistant cell lines, i.e., AZDR3, AZDR6, AZDR9, AZDR11, and AZDR14. The amplification of wild-typeEGFRin AZDR3 cells and wild-type EGFR and KRAS in AZDR6 cells was also studied. AZDR3 cells showed dependence on EGFR signaling, in addition to afatinib sensitivity. AZDR9 cells harboringKRASG13Dshowed sensitivity to MEK inhibitors. Furthermore, combination treatment with EGFR and IGF1R inhibitors resulted in attenuated cell proliferation and enhanced apoptosis. In AZDR11 cells, increased Bim expression could not induce apoptosis, but Bid cleavage was found to be essential for the same. A SHP2/T507K mutation was also identified in AZDR14 cells, and, when associated with GAB1, SHP2 could activate ERK1/2, whereas a SHP2 inhibitor, TNO155, disrupted this association, thereby inhibiting GAB1 activation. Thus, diverse osimertinib resistance mechanisms were identified, providing insights for developing novel therapeutic strategies for NSCLC.
2. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C
Pascal Rigollier, Xiaoming Cui, Edwige Lorthiois, Peter Wessels, Nils Ostermann, Richard Sedrani, Lekshmi Dharmarajan, Jason Murphy, Helen Oakman, Christian Schnell, Louise Barys, Sauveur-Michel Maira, Danielle Roman, Xueying Chen, Toshio Shimizu, Toni Widmer, Anna F Farago, Ashley Jaeger, Heather Burks, Andrea Vaupel, Rainer Wilcken, Catherine Leblanc, Carmine Fedele, Eloísa Jiménez Núñez, Andreas Weiss, Johannes Ottl, Ruben de Kanter, Rowan Stringer, Jeffrey D Kearns, Frederic Zecri, Hans Voshol, Kun Xu, Saskia M Brachmann, Daniel Alexander Guthy, Claudio Bomio-Confaglia, Marc Gerspacher, Simona Cotesta, Victoria Head, Kim S Beyer Cancer Discov . 2022 Jun 2;12(6):1500-1517. doi: 10.1158/2159-8290.CD-22-0158.
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors.Significance:JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.
3. Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer
Denise Grunenfelder, Jianmei Fan, Mark Palermo, Christopher Straub, Travis Stams, Shumei Liu, Morvarid Mohseni, Sarah L Williams, Ying-Nan Chen, Timothy Ramsey, Victoriano Tamez Jr, William R Sellers, Cary Fridrich, Mitsunori Kato, Gang Liu, Meir Glick, Michelle Fodor, Martin Hentemann, Andriana Jouk, Martin Sendzik, John Reilly, Simon Mathieu, Julie Boisclair, Suzanne Zhu, Bakary-Barry Toure, Zhao B Kang, Joanna Slisz, Minying Pu, Rukundo Ntaganda, Laura R LaBonte, Brant Firestone, Zhan Deng, Lawrence Perez, Kelly Slocum, Peter Fekkes, Homan Chan, Fan Yang, Ping Wang, Ji-Hu Zhang, Daniel Bauer, Hongyun Wang, Samuel Ho, Matthew J Meyer, Matthew J LaMarche, Rajesh Karki, Zhouliang Chen, Robert Koenig, Jay Larrow, Patrick Sarver, Michael Acker, Troy Smith, Stanley Spence, Huia-Xiang Hao, Christine Hiu-Tung Chen, Dyuti Majumdar, David Dunstan, Nick Keen, Michael Dore, Michael D Shultz, Christopher Towler, Andreea Argintaru, Bing Yu, Pascal D Fortin, Jorge Garcia-Fortanet, John Giraldes J Med Chem . 2020 Nov 25;63(22):13578-13594. doi: 10.1021/acs.jmedchem.0c01170.
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by thePTPN11gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potentin vivoantitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
