Abstract
Abstract FUS1, a novel tumor suppressor gene in the human chromosome 3p21.3 region, is deleted in many cancers. A phase I clinical trial assessing FUS1-mediated molecular therapy has reported antitumor activity in lung cancer patients. Previous studies showed that FUS1 regulates the activation of multiple oncogenic kinases. MK2206 is a highly selective non-ATP-competitive allosteric inhibitor of AKT currently being evaluated in early-phase clinical trials for treatment of patients with lung cancer. In this study, we evaluated the combined effects of the tumor suppressor gene FUS1 and MK2206 on tumor cell growth and apoptosis induction in NSCLC cells and explored the molecular mechanism of their mutual action. We found that exogenous expression of FUS1 sensitized the response of NSCLC cells to MK2206, resulting in a marked increase in growth suppression and apoptosis in LKB1-mutant NSCLC cells. However, FUS1 had no effect on the response of LKB1-wild-type NSCLC cells to MK2206. Systemic treatment with a combination of FUS1-nanoparticles and MK2206 in an LKB1 mutant H322 lung cancer subcutaneous xenograft mouse model enhanced the therapeutic efficacy of MK2206. The mice receiving the combination of MK2206 and FUS1-nanoparticles showed a significantly reduced mean tumor volume (364±164 mm3) compared with mice receiving empty vector/MK2206 (728±101 mm3), MK2206 alone (926±250 mm3), FUS1 alone (1171±294 mm3), or empty vector (2405±737 mm3) by day 21 (P<0.01 for all three comparisons). Our results show that FUS1 may play a role in modulating the sensitivity of lung cancer cells to AKT inhibition, and suggests that a combination of FUS1-nanoparticles and MK2206 may be an effective treatment strategy for LKB1 mutant human lung cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 870. doi:1538-7445.AM2012-870
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