Abstract 5605: LKB1 and KRAS mutations predict resistance to PI3K/Akt inhibitors in non-small cell lung cancer

Abstract

Abstract Background: LKB1 and KRAS are the most commonly mutated genes in non-small cell lung cancer (NSCLC), each present in up to 35% of patient tumors. KRAS mutations have been associated with resistance to EGFR tyrosine kinase inhibitors, but it is not established to what extent KRAS or LKB1 mutations may predict response to other systemic treatments, including PI3K/Akt and MEK inhibitors. Methods: IC50s for cytotoxic chemotherapies and targeted drugs were determined by MTS assay in a large panel of NSCLC cell lines with known mutational status. Cells lines with and without mutations were compared by t-test and linear mixed model to determine the effect of single and double mutations. Protein expression in cell lines was measured by reverse phase protein array. Results: LKB1 mutations strongly predicted resistance to Akt inhibition by MK2206 (p=0.004), but not to PI3K inhibitors BAY80-6949, GDC0941, or 8-amino-adenosine (p>0.24). In contrast, KRAS mutations were strongly associated with resistance to PI3K inhibitors BAY80-6949 (p≤0.0001) and GDC0941 (p=0.034) and to Akt inhibition by MK2206 (p=0.047). Conversely, there was a trend towards greater sensitivity in the KRAS mutated cells to the MEK inhibitor BAY86-9766. Resistance to PI3K inhibition in KRAS mutated lines was largely abrogated by the combination of BAY80-6949 and BAY86-9766. Co-existing LKB1 and KRAS mutations were present in 18% of cell lines, but were not significantly more resistant to PI3K/Akt inhibitors, nor did they predict greater MEK inhibitor sensitivity. There was no association between KRAS or LKB1 mutations and response to cytotoxic chemotherapies, including docetaxel, pemetrexed, or platinum doublets. At the protein level, LKB1 mutant cell lines had significantly higher expression of IGF1R (p<0.0001 by t-test), compared to wild type cell lines, which may represent an alternative signaling pathway contributing to resistance in mutant cell lines. Conclusions: KRAS and LKB1 mutations are associated with greater resistance to PI3K/Akt inhibitors, although there are some differences in resistance with specific drugs. These findings suggest that these mutations may have potential as predictive biomarkers and warrant further investigation prospectively in clinical trials of PI3K, Akt, and MEK inhibitors. In addition, the observation of increased protein expression of IGFR1 in LKB1 mutated lines supports a rationale for combining PI3K/Akt and IGF1R inhibitors as a strategy to overcome resistance. 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 5605. doi:1538-7445.AM2012-5605