Abstract 2449: Identifying therapy responsive and resistant LKB1 mutant non-small cell lung tumor populations
Authors: Abt Evan , Momcilovic Milica , Seki Atsuko , McMickle Robert , Stout David , Fishbein Michael C. , Shackelford David B. 
Published: May 2015

Abstract
The LKB1/STK11 tumor suppressor is mutationally inactivated in ∼30% of sporadic non-small cell lung cancers (NSCLC), and to date there are no agents targeting loss of LKB1 in lung cancer. LKB1 is the major upstream kinase activating the energy sensing kinase AMPK under conditions of low intracellular ATP. In cells defective for LKB1, metabolic stress is not appropriately sensed and energy homeostasis is not efficiently restored, providing an Achilles heel to target in tumors with this genetic lesion. Importantly, LKB1-deficient (LKB1-/-) NSCLC cells are unable to restore energy homeostasis in response to biguanide-induced energy stress and preferentially undergo apoptosis. As targeted therapy for LKB1 mutant tumors are needed, we explored the use of the metabolic stress agent phenformin as an anti- cancer drug to target the LKB1-/- NSCLC. Phenformin is a biguanide that has historically used to treat metabolic disease and we demonstrated that it potently induced apoptosis in LKB1-/- lung tumors and significantly prolonged survival in genetically engineered mouse models (GEMMs) of lung cancer in mice bearing tumors with mutated Kras and Lkb1 genes but not mice with compound mutations in Kras and p53. Our pre-clinical studies suggest phenformin may be used as a cancer metabolism-based prevention agent or therapeutic to selectively target LKB1-/- pulmonary epithelial cells and tumors. However, phenformin as a single agent therapy was not curative, highlighting the need to find additional therapies to prevent or target LKB1-/- lung tumors in combination with phenformin. We have previously shown LKB1 loss leads to mTORC1 hyperactivation therefore we explored the combinatorial use of phenformin with the mTOR kinase inhibitor MLN128. We tested phenformin and MLN128 together on our human and mouse models of lung cancer and demonstrated the two drugs cooperated together to enhance apoptosis and reduce proliferation. KrasG12D driven, Lkb1-/- mice develop both adenocarcinoma (ADC) and squamous cell carcinomas (SQCC). We performed 18FDG-PET and CT guided pre-clinical studies assessing phenformin + MLN128 as a combinatorial therapy in vivo using our Lkb1-/- GEMMs of NSCLC. We discovered that lung ADC were highly responsive to the combination therapy while the SQCC lung tumor populations appear highly resistant. These findings carry important clincal relevance as currently there are limited options for patients with LKB1-mutant tumors. Here we define the hypersensitivity of LKB1-/- lung ADC tumors to metabolic stress and mTOR inhibition while in parallel identifying a therapy resistant SQCC lung tumor population. These results suggest phenformin in combination with mTOR kinase inhibitors may find clinical utility to treat LKB1 mutant lung ADC.
Citation Format: Evan Abt, Milica Momcilovic, Atsuko Seki, Robert McMickle, David Stout, Michael C. Fishbein, David B. Shackelford. Identifying therapy responsive and resistant LKB1 mutant non-small cell lung tumor populations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2449. doi:10.1158/1538-7445.AM2014-2449