Sonya C. Tate (1), Teresa Burke (2), Shufen Cai (2), Daisy Hartman (2), Palaniappan Kulanthaivel (2), Lawrence M. Gelbert (2), Richard P. Beckmann (2), Damien M. Cronier (1)
(1) Eli Lilly and Company, Windlesham, United Kingdom; (2) Eli Lilly and Company, Indianapolis, IN, USA
Objectives: Although vemurafenib demonstrates excellent clinical efficacy in the first-line treatment of BRAF V600E-mutated metastatic melanoma [1], resistance ultimately develops and patients relapse [2]. Experimental evidence in resistant melanoma cells indicates that MAPK pathway reactivation is a primary mechanism for resistance [3,4]; however recent studies indicate that the acquisition of resistance may also be associated with an activation of the CDK4/6 pathway through upregulation of cyclin D1 [5,6]. Consistent with these findings, CDK4/6 inhibition by LY2835219 overcomes resistance and produces tumour growth inhibition in vemurafenib-resistant A375 melanoma xenografts [6]. The objective of this study is to develop an integrated pharmacokinetic (PK)/pharmacodynamic (PD) model to characterize resistance to vemurafenib and its rescue by LY2835219 in A375 tumour xenografts.
Methods: The semi-mechanistic PK/PD model previously developed to describe cell cycle inhibition by LY2835219 [7] was extended to include vemurafenib-mediated BRAF inhibition on the MAPK pathway. Tumour shrinkage induced by vemurafenib was described by inhibition of pERK (major route) and pHH3 (minor route). A modulator compartment driving time-dependent upregulation of the MAPK pathway was incorporated to account for emerging vemurafenib resistance and increasing sensitivity to total Rb. Finally, rescue by LY2835219 was associated with LY2835219-mediated inhibition of total Rb.
Results: Vemurafenib-mediated tumour shrinkage was adequately described by the extended biomarker model. Inhibition of pERK was confirmed to be the primary contributor to tumour shrinkage, and a minor contribution of cyclin D1-mediated cell cycle arrest was identified. Resistance to vemurafenib was successfully accounted for by time-dependent over-expression of pMEK, pERK and cyclin D1. More importantly, inclusion of cyclin D1-mediated sensitivity to total Rb allowed LY2835219-mediated rescue of tumour shrinkage in resistant cells to be successfully characterised.
Conclusions: The PK/PD model successfully described the effect of LY2835219 in vemurafenib-resistant A375 melanoma xenografts. Vemurafenib anti-tumour effect and tumour resistance, followed by LY2835219-mediated rescue were described by an integrated semi-mechanistic PK/PD model. These results support the hypothesis that vemurafenib -resistant melanoma cells rely on total Rb levels for survival and support further exploration of the combination of LY2835219 and RAF inhibitors in melanoma.
References:
[1] Chapman, P.B., et al., Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med, 2011. 364(26): p. 2507-16.
[2] Flaherty, K.T., et al., Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med, 2010. 363(9): p. 809-19.
[3] Nazarian, R., et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature, (2010) 468: p. 973-977.
[4] Su, F., et al. Resistance to Selective BRAF Inhibition Can Be Mediated by Modest Upstream Pathway Activation. Cancer Res, (2012) 72: p.969-978.
[5] Smalley, K.S., et al., Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther, 2008. 7(9): p. 2876-83.
[6] Yadav et al., The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Abs # C88, 991, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Oct 19-23, 2013, Boston, MA.
[7] Tate, S.C., et al., Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the anti-tumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts. Forthcoming.
Reference: PAGE 23 (2014) Abstr 3268 [www.page-meeting.org/?abstract=3268]
Poster: Drug/Disease modeling - Oncology