Abstract PR03: Extended inhibition of CDK4/6 inhibits mTORC1 signaling and induces therapeutic senescence in vemurafenib resistant melanoma

Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle within 24h and continued exposure for 8-days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAFV600E inhibitor, has significant clinical efficacy in BRAFV600E positive melanomas but its impact is hampered by a rapid acquisition of resistance. Strikingly, we found that vemurafenib-resistant tumors remain sensitive to palbociclib suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an avenue to overcome recurrence of vemurafenib resistant, metastatic disease. Taken together these results support palbociclib as a promising therapeutic for treatment of melanoma.This abstract is also being presented as Poster A14.Citation Format: Akihiro Yoshida, J. Alan Diehl. Extended inhibition of CDK4/6 inhibits mTORC1 signaling and induces therapeutic senescence in vemurafenib resistant melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AA...

Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Yoshida, A., Diehl, J. A. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Oral Presentations - Proffered Abstracts Source Type: research