Levels of p27kip1 determine Aplidin sensitivity.

Abstract

Aplidin (plitidepsin) is a novel anticancer drug isolated from themarine tunicate Aplidiumalbicans. Aplidin shows potent antitumor activity in preclinical models against awide variety of human tumors. Aplidin is currently inphase II clinical trials in a varietyof solid tumorsandhematologicmalignancies.Moreover,clinical studiesofAplidin incombinationwithother agentsare ongoingbecause itgenerally lackscross-resistancewith other known cytotoxic drugs. Themode of action of Aplidinintumorcellsisonlypartiallyunderstood.Aplidin inducesanearlyoxidativestressresponse,whichresults inarapidandsustainedactivationoftheepidermalgrowth factor receptor, thenonreceptor protein tyrosinekinase Src,andtheserinethreoninekinasesc-JunNH2-terminal kinaseandp38mitogen-activatedproteinkinase.Here, weshowthat sensitivity toAplidincorrelates inversely with the levels of expression of the cyclin-dependent kinase inhibitorp27kip1 (p27) inapanelof lowpassaged humansarcomacell lines.Aplidin inducesp27 through anoxidation-dependentmechanismandthereductionof p27levelsbyspecificshorthairpinRNAincreasesAplidin sensitivity.Weconfirmedtheseresultsinp27nullmouse embryonicfibroblastscorroboratingthespecificityof the p27roleinAplidinresponsebecausep21waf1nullmouse embryonic fibroblastsdonot showthis increasedsensitivity.We propose amechanismof action of Aplidin involving p27 and support the analysis of p27 in the responsetoAplidin incurrentlyongoingclinical trials to establishthe levelsof thisproteinasresponsepredictor.