Targeting tumor cell mitochondria for the prevention and treatment of lung cancer

Lung cancer is the leading cause of cancer-related mortality in the United States and adenocarcinoma (ADC) is the most common histological type of lung cancer. Kras mutations occur in 20–40% of lung ADCs and, among Kras-mutant lung tumors (K tumors), concurrent mutations of Kras and the tumor suppressor gene LKB1 (KL tumors) ranged from 8% to 31%. Loss of function of LKB1 can also be induced through DNA methylation and phosphorylation of wild-type LKB1. Lung tumors induced by tobacco smoke and tobacco smoke carcinogens exhibit Kras mutation and methylation/phosphorylation of LKB1, thereby sharing several features with KL tumors. Tumors with alterations in both Kras and LKB1 are highly aggressive and not amenable to existing therapies, including immunotherapy. Therefore, the long-term goal of this application is to develop novel, safe and effective agents for the prevention and therapy of KL tumors. Since KL lung tumors are characterized by high levels of metabolic and oxidative stress, further enhancement oxidative stress through small molecules may preferentially induce the death of cancer cells due to their inherent vulnerability to oxidative stress. We hypothesize that mitomet, a mitochondria-targeted metformin analog, which selectively accumulates in the mitochondria of tumor cells and induces energetic and redox stress prevents malignant progression of lung tumors with co-occurring Kras and LKB1 alterations and sensitize these tumors to immune checkpoint blockade, in KL tumors. Our hypothesis is supported by extensive preliminary data. On the basis of these preliminary findings, we propose the following Specific Aims. Specific Aim 1: Assess the safety of mitomet and determine its efficacy to suppress malignant progression of NNK-induced lung tumors in mice. Specific Aim 2: Determine the efficacy of mitomet to suppress malignant progression of mouse lung tumors with co-occurring Kras and LKB1 mutations and to modulate the tumor immune microenvironment and thereby reverse the resistance of KL tumors to immunotherapy. Specific Aim 3: Compare the tumor propagating potential of CD44+ CD133+ and CD44—CD133— fractions of mouse KL tumor cells and assess if mitomet and/or immunotherapy suppress the tumor propagating capacity of CD44+ CD133+ mouse KL tumor cells. Tumor cells for these studies will be obtained from Aim 2. This proposal will elucidate whether Kras mutation and LKB1 loss-associated energetic and redox stress renders KL tumor cells differentially sensitive to mitomet. The results of these studies will lay the groundwork for future clinical trials of mitomet for the prevention and therapy of human KL lung cancer.