Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation

// Ryan E. Henry 1,* , Evan R. Barry 1,* , Lillian Castriotta 1 , Brendon Ladd 1 , Aleksandra Markovets 1 , Garry Beran 2 , Yongxin Ren 3 , Feng Zhou 3 , Ammar Adam 1 , Michael Zinda 1 , Corinne Reimer 1 , Weiguo Qing 3 , Weiguo Su 3 , Edwin Clark 1 , Celina M. D’Cruz 1 and Alwin G. Schuller 1 1 AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA 2 AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Alderley Park, UK 3 Hutchison Medi Pharma Ltd, Zhangjiang Hi-Tech Park, Shanghai, China * These authors have contributed equally to this work Correspondence to: Alwin G. Schuller, email: // Celina M. D’Cruz, email: // Keywords : MET, MYC, NSCLC, acquired resistance, savolitinibReceived : January 14, 2016 Accepted : July 13, 2016 Published : July 26, 2016 Abstract Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. The receptor tyrosine kinase MET has been implicated as an oncogene in numerous cancer subtypes, including non-small cell lung cancer (NSCLC). Here we explore the therapeutic potential of savolitinib(volitinib, AZD6094, HMPL-504), a potent and selective MET inhibitor, in NSCLC. In vitro , savolitinibinhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo , savolitinibcauses inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinibresistance in MET -amplified NSCLC cell lines and analyzed individual clones. We found that upregulation of MYC and constitutive mTOR pathway activation is a conserved feature of resistant clones that can be overcome by knockdown of MYC or dual mTORC1/2 inhibition. Lastly, we demonstrate that mechanisms of resistance are heterogeneous, arising via a switch to EGFR dependence or by a requirement for PIM signaling. This work demonstrates the efficacy of savolitinibin NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic.