Abstract C88: The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation.

Abstract

Abstract B-RAFV600E mutation is found in approximately 50% of melanoma patients. It activates the MEK/ERK pathway and drives tumor progression. Vemurafenib, a B-RAF selective inhibitor was recently approved as an effective therapy for metastatic melanoma with B-RAF V600E mutation. However, most patients treated with vemurafenib eventually develop resistance in an average of 6-7 months. We and others have found that MAPK reactivation is a common mechanism of vemurafenib resistance. However, inhibitors of MAPK pathway, such as the MEK inhibitor trametinib, showed minimal clinical benefit in patients who had previously developed resistance to vemurafenib. Thus, overcoming resistance to vemurafenib remains an urgently unmet medical need. In this report, we have developed several in vitro models and an in vivo model resistant to vemurafenib and found that, in addition to MAPK reactivation, Cyclin D1 upregulation is common in these models. We demonstrated that these resistant cells are sensitive to inhibition of the Cyclin D1-CDK4/6 axis by LY2835219, a selective CDK4/6 inhibitor. LY2835219 inhibited growth of melanoma A375 xenografts, and delayed tumor recurrence in combination with vemurafenib. We further developed a vemurafenib-resistant xenograft model by continuous dosing of vemurafenib in A375 xenografts. Consistent with our in vitro observation, we found that Cyclin D1 is elevated and the MAPK pathway is reactivated in the resistant tumors, as well as in the cell lines generated from these tumors. Importantly, treatment with LY2835219 induced significant growth inhibition in these vemurafenib-resistant tumors. Additional mechanistic analysis demonstrated that LY2835219 preferably induced apoptosis in vemurafenib-resistant cells, while it primarily arrested cells in G1 phase in the parental A375 cells. Similar to CDK4/6 inhibition by LY2835219, Cyclin D1 knockdown by siRNA also induced a significantly higher rate of apoptotic cell death in the resistant cells, suggesting that Cyclin D1 may play an important role in the survival of resistant cells. Altogether, our data suggest that inhibition of the Cyclin D1-CDK4/6 axis by LY2835219 represents an effective strategy for overcoming resistance to B-RAF inhibition in melanoma patients with oncogenic BRAF mutation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C88. Citation Format: Vipin Yadav, Teresa F. Burke, Lysiane Huber, Robert D. Van Hoen, Youyan Zhang, Sean Buchanan, Edward M. Chan, James J. Starling, Richard P. Beckmann, Sheng-Bin Peng. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C88.