Effects of LKB1 Mutation and mTOR Inhibition on IGFR1 Pathway in Non-small Cell Lung Cancer


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LKB1 is a serine/threonine kinase that has been found to be mutated in approximately 20% to 30% of patients with non–small cell lung cancer (NSCLC). LKB1 acts as a tumor suppressor by activating AMPK, and loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling.

LKB1 Mutation Increases IGFR1 Pathway Proteins

Emrullah Yilmaz, MD, in collaboration with John V. Heymach, MD, PhD, at The University of Texas MD Anderson Cancer Center, investigated the effects of LKB1 mutation and mTOR inhibition on cell signaling pathways, measuring protein expression in NSCLC cell lines by reverse phase protein array.1 They found that LKB1 mutant cell lines had significantly lower expression of phosphorylated AMPK and tuberous sclerosis complex compared with LKB1 wild-type cell lines (P < .01), consistent with prior observations. In addition, mutant cell lines expressed higher levels of proteins in the insulin-like growth factor 1 receptor (IGFR1) pathway, including IGFR1b (P < .0001), amplified in breast cancer-1 (AIB1)—which is known to upregulate IGF1 (P < .0001), and IGF binding protein 2 (IGFBP2) (P = .016).

AMPK Activation and mTOR Inhibition

LKB1 mutant cell lines were 1.5-fold more sensitive to the AMPK activator metformin than wild-type LKB1 cell lines, although the difference was not significant (P = .10). Expression levels of IGFR1 pathway proteins increased significantly after 48 hours of treatment with metformin, the mTOR inhibitor temsirolimus (Torisel), and the dual PI3K/mTOR inhibitor PI103, with the modulation of the IGFR1 pathway by these drugs being independent of LKB1 mutation status.

IGFBP2 and AIB1 were elevated after metformin treatment (P = .02 and P = .005, respectively), and insulin receptor substrate-1 and IGFR1 were elevated after temsirolimus or PI-103 treatment (P < .05 for both). Treatment with metformin and temsirolimus (P < .01 for both) also increased expression of phosphorylated Akt, which is a downstream target of IGFR1 and an mTOR activator.

As stated by the investigators, “LKB1 mutant cell lines have increased IGFR activity with higher baseline IGFR1, IGFBP2, and AIB1, suggesting that IGFR may be a potential therapeutic target in LKB1 mutant tumors. In addition, inhibition of the mTOR pathway upregulates the IGFR pathway, possibly as a feedback mechanism. These results support the investigation of IGFR inhibitors in combination with drugs targeting the mTOR pathway, particularly for tumors bearing LKB1 mutations.” ■

Disclosure: The investigators reported no potential conflicts of interest.

Reference

1. Yilmaz E, Byers LA, Diao L, et al: 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. 2012 ASCO Annual Meeting. Abstract 10612. Presented June 4, 2012.



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