title: Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation.
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, savolitinib inhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo, savolitinib causes inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinib resistance 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 savolitinib in NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic.
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Henry
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Barry
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Castriotta
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Brendon
authors.initials: B
authors.lastname: Ladd
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Markovets
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Alderley Park, UK.
authors.forename: Garry
authors.initials: G
authors.lastname: Beran
authors.affiliation: Hutchison Medi Pharma Ltd, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Hutchison Medi Pharma Ltd, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Ammar
authors.initials: A
authors.lastname: Adam
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.affiliation: Hutchison Medi Pharma Ltd, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Qing
authors.affiliation: Hutchison Medi Pharma Ltd, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Su
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Clark
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Celina M
authors.initials: CM
authors.lastname: D'Cruz
authors.affiliation: AstraZeneca Pharmaceuticals PLC, Oncology Bioscience, Waltham, MA, USA.
authors.forename: Alwin G
authors.initials: AG
authors.lastname: Schuller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011719:Pyrazines / Q000737:chemistry*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014227:Triazines / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C489427:MYC protein, human; C000593259:1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; C546842:MTOR protein, human; C512478:EGFR protein, human; C491743:MET protein, human
keywords: MET; MYC; NSCLC; acquired resistance; savolitinib