Reference Detail

Ref Type Journal Article
PMID (26574479)
Authors Momcilovic M, McMickle R, Abt E, Seki A, Simko SA, Magyar C, Stout DB, Fishbein MC, Walser TC, Dubinett SM, Shackelford DB
Title Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers.
Journal Cancer research
Vol 75
Issue 22
Date 2015 Nov 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
STK11 E57Sfs*107 mTOR Inhibitor
STK11 I35Lfs*127 mTOR Inhibitor
STK11 Y272H mTOR Inhibitor
STK11 T250P mTOR Inhibitor
STK11 D277Y mTOR Inhibitor
STK11 D194Y mTOR Inhibitor
STK11 Y118* mTOR Inhibitor
STK11 Q220* mTOR Inhibitor
STK11 G56Tfs*4 mTOR Inhibitor
STK11 P281Rfs*6 mTOR Inhibitor
STK11 K62Sfs*100 mTOR Inhibitor
STK11 Q159* mTOR Inhibitor
STK11 Y60* mTOR Inhibitor
STK11 D176N mTOR Inhibitor
STK11 D176Y mTOR Inhibitor
STK11 L285Q mTOR Inhibitor
STK11 inact mut mTOR Inhibitor
STK11 K84* mTOR Inhibitor
STK11 L285Lfs*2 mTOR Inhibitor
STK11 L67P mTOR Inhibitor
STK11 E223V mTOR Inhibitor
STK11 E120* mTOR Inhibitor
STK11 E70* mTOR Inhibitor
STK11 E165* mTOR Inhibitor
STK11 E57fs mTOR Inhibitor
STK11 E199K mTOR Inhibitor
STK11 K78I mTOR Inhibitor
STK11 Q123* mTOR Inhibitor
STK11 D194E mTOR Inhibitor
STK11 M136R mTOR Inhibitor
STK11 S216F mTOR Inhibitor
STK11 A218Sfs*42 mTOR Inhibitor
STK11 D53Tfs*11 mTOR Inhibitor
STK11 K44* mTOR Inhibitor
STK11 K78A mTOR Inhibitor
STK11 Q170* mTOR Inhibitor
STK11 Q137* mTOR Inhibitor
STK11 K48fs mTOR Inhibitor
STK11 G171S mTOR Inhibitor
STK11 Q37* mTOR Inhibitor
STK11 I177N mTOR Inhibitor
STK11 A205T mTOR Inhibitor
STK11 P281fs mTOR Inhibitor
STK11 P281L mTOR Inhibitor
STK11 E65* mTOR Inhibitor
STK11 R304W mTOR Inhibitor
STK11 N181E mTOR Inhibitor
STK11 E138* mTOR Inhibitor
STK11 P281Pfs*4 mTOR Inhibitor
STK11 W308C mTOR Inhibitor
STK11 G61Afs*3 mTOR Inhibitor
STK11 G163D mTOR Inhibitor
STK11 Q214* mTOR Inhibitor
STK11 D207Gfs*59 mTOR Inhibitor
STK11 H174R mTOR Inhibitor
STK11 E199* mTOR Inhibitor
STK11 Q100* mTOR Inhibitor
STK11 E33* mTOR Inhibitor
STK11 L282Afs*3 mTOR Inhibitor
STK11 S240* mTOR Inhibitor
STK11 K62* mTOR Inhibitor
STK11 E121* mTOR Inhibitor
STK11 loss mTOR Inhibitor
STK11 F157S mTOR Inhibitor
STK11 E223* mTOR Inhibitor
STK11 Q170P mTOR Inhibitor
STK11 F354L mTOR Inhibitor
STK11 L245R mTOR Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS G12D STK11 inact mut lung cancer sensitive Sapanisertib Preclinical Actionable In a preclinical study, Sapanisertib (MLN0128) inhibited lung tumor growth in mouse models with KRAS G12D and inactivation of STK11 (LKB1), and demonstrated limited efficacy in tumors with KRAS G12D and wild-type STK11 (PMID: 26574479). 26574479
KRAS mut STK11 inact mut lung adenocarcinoma sensitive Phenformin + Sapanisertib Preclinical Actionable In a preclinical study, Sapanisertib (MLN0128) in combination with phenformin induced apoptosis and energetic stress in human lung adenocarcinoma cell lines with concurrent KRAS and STK11 (LKB1) mutations in culture, with higher levels than either therapy as a single agent (PMID: 26574479). 26574479