Mammalian target of rapamycin signaling and autophagy: roles in lymphangioleiomyomatosis therapy.
The pace of progress in lymphangioleiomyomatosis (LAM) is remarkable. In the year 2000, TSC2 gene mutations were found in LAM cells; in 2001 the tuberous sclerosis complex (TSC) genes were discovered to regulate cell size in Drosophila via the kinase TOR (target of rapamycin); and in 2008 the results were published of a clinical trial of rapamycin, a specific inhibitor of TOR, in patients with TSC and LAM with renal angiomyolipomas. This interval of just 8 years between a genetic discovery for which the relevant signaling pathway was as yet unknown, to the initiation, completion, and publication of a clinical trial, is an almost unparalleled accomplishment in modern biomedical research. This robust foundation of basic, translational, and clinical research in TOR, TSC, and LAM is now poised to optimize and validate effective therapeutic strategies for LAM. An immediate challenge is to deduce the mechanisms underlying the partial response of renal angiomyolipomas to rapamycin, and thereby guide the design of combinatorial approaches. TOR complex 1 (TORC1), which is known to be active in LAM cells, is a key inhibitor of autophagy. One hypothesis, which will be explored here, is that low levels of autophagy in TSC2-null LAM cells limits their survival under conditions of bioenergetic stress. A corollary of this hypothesis is that rapamycin, by inducing autophagy, promotes the survival of LAM cells, while simultaneously arresting their growth. If this hypothesis proves to be correct, then combining TORC1 inhibition with autophagy inhibition may represent an effective clinical strategy for LAM.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, One Blackfan Circle, Boston, MA 02115, USA.
Jane
J
Yu
Andrey A
AA
Parkhitko
Elizabeth Petri
EP
Henske
D018207:Angiomyolipoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012129:Respiratory Function Tests; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus