Abstract C264: Effective preclinical treatment of KRAS mutant lung cancers with a combination of MLN0128, an investigational novel mTORC1/2 inhibitor, and a selective MEK inhibitor.

A component of heterogeneity of human cancers is the presence of multiple mutations that can activate a number of signaling pathways that leads to growth and survival including both MAPK (RAS/RAF/MEK/ERK) and PI3K/Akt/mTOR. Previous preclinical and clinical studies have found that KRAS mutant cancers demonstrate a heterogeneous response to inhibitors targeting the MAPK pathway. The molecular mechanisms responsible for this heterogeneous response remain unclear. KRAS mutations are observed in more than 25% of NSCLC and can occur concurrently with LKB1 or PIK3CA and LKB mutations. Due to the presence of these complex genotypes and the resultant concomitant activation of different signaling pathways, it has become evident that inhibiting a single node remains insufficient to achieve a sustained anti-tumor response. These findings suggest the need to combine different targeted agents to overcome pathway cross talk and feedback activation that has been observed in the single agent setting. Using KRAS driven NSCLC as a model we have postulated that the combination of a mTORC1 / 2 inhibitor and a MEK inhibitor (MLN0128 + TAK-733) could provide improved activity over either agent alone in preclinical models. The effect of this combination on in vitro growth in a panel of NSCLC cell lines was assessed. Synergistic to additive inhibition of proliferation was observed with administration of the combination MLN0128 + TAK-733 over single agent effects in cell lines with KRAS and LKB1, or KRAS combined with PIK3CA and LKB mutations, while no additive inhibition was observed in wild-type cells. An increase in apoptosis, as measured by cleaved PARP, and reduced expression of cyclin D1 relative to single agents alone was also demonstrated after administration of MLN0128 +TAK-733, which likely contributes to the observed decreased tumor cell proliferation observed with the combination. The in vivo anti-tumor activity of MLN0128 + TAK-733 was examined in 2 human tumor xenograft models of NSCLC. Administration of the combination of MLN0128 + TAK-733 improved anti-tumor activity in NCI-H460 (KRAS, PIK3CA and LKB) over single agent administration. In the A549 (KRAS and LKB1) model, the administration of the combination of MLN0128 + TAK-733 using various dosing regimens resulted in reduction in tumor volume in all schedules examined compared to tumor stasis following single agent administration. Overall, these data support further research of the combination of MLN0128 (mTORC1/2) and MEK inhibitors for KRAS plus LKB1 or KRAS plus PIK3CA and LKB mutated NSCLC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C264. Citation Format: Robyn Fabrey, Joy Atienza, David Briere, Rachael Brake, Patrick W. Vincent. Effective preclinical treatment of KRAS mutant lung cancers with a combination of MLN0128, an investigational novel mTORC1/2 inhibitor, and a selective MEK inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C264.