title: Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers.
abstract: Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mTOR complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing comutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas and squamous cell carcinomas (SCC). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1-mutant human cell lines and genetically engineered mouse models of NSCLC that develop both adenocarcinomas and SCCs. Specifically, we found that KRAS/LKB1-mutant lung adenocarcinomas responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors, thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1-mutant adenocarcinomas and squamous cell tumors.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Milica
authors.initials: M
authors.lastname: Momcilovic
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Robert
authors.initials: R
authors.lastname: McMickle
authors.affiliation: Department of Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Evan
authors.initials: E
authors.lastname: Abt
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Seki
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Simko
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Clara
authors.initials: C
authors.lastname: Magyar
authors.affiliation: Department of Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: David B
authors.initials: DB
authors.lastname: Stout
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Walser
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, California. Department of Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
authors.affiliation: Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, California. DShackelford@mednet.ucla.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Shackelford
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001583:Benzoxazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D010629:Phenformin / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D013312:Stress, Physiological / Q000187:drug effects*; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D001583:Benzoxazoles; D010629:Phenformin; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D011743:Pyrimidines; C117307:KRAS protein, human; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; C495971:Hras protein, mouse; C572449:sapanisertib; D000225:Adenine