The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation
Menée in vitro et in vivo, cette étude suggère l'intérêt d'un composé appelé LY835219, un inhibiteur de la cycline CDK4/6, pour surmonter une résistance au vemurafenib chez les patients atteints d'un mélanome présentant la mutation V600E du gène B-RAF
B-RAF selective inhibitors including vemurafenib were recently developed as effective therapies for melanoma patients with B-RAF V600E mutation. However, most patients treated with vemurafenib eventually develop resistance largely due to reactivation of MAPK signaling. Inhibitors of MAPK signaling including MEK1/2 inhibitor trametinib failed to show significant clinical benefit in patients with acquired-resistance to vemurafenib. Here we describe that cell lines with acquired-resistance to vemurafenib show reactivation of MAPK signaling and upregulation of cyclin D1, and are sensitive to inhibition of LY2835219, a selective inhibitor of cyclin dependent kinase (CDK) 4/6. LY2835219 was demonstrated to inhibit growth of melanoma A375 tumor xenografts, and delay tumor recurrence in combination with vemurafenib. Furthermore, we developed an in vivo vemurafenib-resistant model by continuous administration of vemurafenib in A375 xenografts. Consistently, we found that the MAPK is reactivated and cyclin D1 is elevated in vemurafenib-resistant tumors, as well as in the resistant cell lines derived from these tumors. Importantly, LY2835219 exhibited tumor growth regression in vemurafenib-resistant model. Mechanistic analysis revealed that LY2835219 induced apoptotic cell death in a concentration dependent manner in vemurafenib-resistant cells while it primarily mediated cell cycle G1 arrest in the parental cells. Similarly, RNAi-mediated knockdown of cyclin D1 induced significantly higher rate of apoptosis in the resistant cells compared to parental cells, suggesting that elevated cyclin D1 activity is important for the survival of vemurafenib resistant cells. Altogether, we propose that targeting cyclin D1-CDK4/6 signaling by LY2835219 is an effective strategy to overcome MAPK-mediated resistance to B-RAF inhibitors in B-RAFV600E melanoma.
http://mct.aacrjournals.org/content/early/2014/08/13/1535-7163.MCT-14-0257.abstract 2014