LKB1 is a serine/threonine kinase located on chromosome 19p13.3. Inherited mutations in LKB1 giverise to Peutz-Jeghers syndrome, a disorder characterized by benign hemartomas of Gl tract and apredisposition to certain cancers, including lung. While acquired mutations in LKB1 are relatively rare inmost sporadic tumor types, more than 30% of NSCLC harbor inactivating mutations in LKB1. Recentprogress on the function of LKB1 places this gene at the apex of a novel signaling pathway that ultimatelyserves to inhibit the mammalian Target of Rapamycin (mTOR). Current evidence supports a model in whichLKB1 mediates the suppression of mTOR through the sequential activation of AMP regulated kinase(AMPK) and the tumor suppressor TSC2, overriding PIS kinase/AKT survival signaling under conditions oflow energy or nutrient deprivation. Data from the literature and preliminary work from our laboratoriesindicate that cells with compromised LKB1 function are more resistant to effects of microtubule-targetedchemotherapeutic agents. These data have led us to hypothesize that LKB1 may act as a sensor ofmicrotubule integrity, and that LKB1 mediated suppression of mTOR activity may promote apoptosis inresponse to microtubule-directed agents. LKB1 is also farnesylated at a CAAX motif in the C-terminus andmay be a target of farnesyltransferase inhibitors. Thus, LKB1 and its downstream effectors may representa convergence point between existing agents like the taxanes that interfere with microtubule dynamics andcontemporary signal transduction inhibitors such as the mTOR inhibitors and the farnesyltransferaseinhibitors.It is our hypothesis that LKB1/AMPK/TSC2 pathway is a frequent target of inactivation in NSCLC andthat the integrity of this pathway is a critical determinant of the sensitivity of NSCLC to selectedchemotherapeutic agents. The goals of this proposal are to (i) determine the frequency of LKB1/AMPKsignaling pathway alterations in NSCLC, (ii) determine the impact of LKB1/AMPK pathway alterations onthe response of NSCLC to selected chemotherapeutic agents, and (iii) determine whetherLKB1/AMPK/TSC pathway alterations are predictive of clinical response to therapeutic agents in NSCLCpatients. A better understanding of the consequences of altered LKB1/AMPK/TSC2 signaling in NSCLCand its role in chemosensitivity will provide novel insight into the mechanism(s) underlying intrinsic drugresistance and may provide a molecular basis for future implementation of 'individualized' therapies.
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