Use of proteomic analysis of LKB1/AMPK/mTOR pathways to identify IGF-1R pathway upregulation with LKB1 loss or mTOR inhibition in NSCLC: Implications for targeted combinations.

10612 Background: LKB1 is a serine/threonine kinase which is mutated in 20-30% of non-small cell lung cancers (NSCLC) and functions as a tumor suppressor by activating AMPK. Loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling. We investigated the signaling pathways modulated by LKB1 mutations and by mTOR inhibition in NSCLC. Methods: Protein expression in cell lines was measured by reverse phase protein array. Differences in protein expression at baseline in LKB1 wild-type versus mutant cell lines and the effects of protein modulation by treatment were assessed by ANOVA. Results: LKB1 mutant cell lines had lower expression of phosphorylated AMPK and TSC (p<0.01 for both) consistent with prior observations. In addition, mutant cell lines expressed higher levels of proteins in the IGF1R pathway including IGFR1b (p<0.0001); AIB1, which is known to upregulate IGF1 (p<0.0001); and IGFBP2 (p=0.016). LKB1 mutant cell lines (n=11/25) were 1.5-fold more sensitive to the ...