title: Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.
abstract: Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Boudreau
authors.affiliation: Discovery Chemistry, Genentech, South San Francisco, California, USA.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Hitz
authors.affiliation: Discovery Chemistry, Genentech, South San Francisco, California, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.affiliation: Discovery Chemistry, Genentech, South San Francisco, California, USA.
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Mandy
authors.initials: M
authors.lastname: Kwong
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hong
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Del Nagro
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Pusapati
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Ma
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California, USA.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Discovery Chemistry, Genentech, South San Francisco, California, USA.
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Chemistry, WuXi AppTec Co., Ltd., Shanghai, China.
authors.forename: Tommy
authors.initials: T
authors.lastname: Lai
authors.affiliation: Structural Biology, WuXi AppTec Co., Ltd., Shanghai, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Structural Biology, WuXi AppTec Co., Ltd., Shanghai, China.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Discovery Chemistry, Genentech, South San Francisco, California, USA.
authors.forename: Binqing
authors.initials: B
authors.lastname: Wei
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: McCleland
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Corson
authors.affiliation: Biomedical Imaging, Genentech, South San Francisco, California, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Vanderbilt
authors.affiliation: Biomedical Imaging, Genentech, South San Francisco, California, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.affiliation: Bioinformatics, Genentech, South San Francisco, California, USA.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Daemen
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.affiliation: Structural Biology, Genentech, South San Francisco, California, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.affiliation: Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Discovery Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.affiliation: Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000066670:Cell Plasticity / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; C000618756:GNE-140; D011728:Pyridones; D013876:Thiophenes; D007770:L-Lactate Dehydrogenase