TY - JOUR
T1 - An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor-based therapies in melanoma
AU - Teh, Jessica L.F.
AU - Purwin, Timothy J.
AU - Greenawalt, Evan J.
AU - Chervoneva, Inna
AU - Goldberg, Allison
AU - Davies, Michael A.
AU - Aplin, Andrew E.
N1 - Funding Information:
M.A. Davies reports receiving a commercial research grant from GSK, Genentech, Merck, Sanofi-Aventis, Astrazeneca, and Myriad and is a consultant/advisory board member for Novartis, Genentech, Sanofi Aventis, and Vaccinex. A.E. Aplin reports receiving a commercial research grant from Pfizer. No potential conflicts of interest were disclosed by the other authors. We thank Neda Dadpey for technical assistance and Dr. Adam Berger for the fresh human melanoma tissue. This study was supported by an Industrial Partnership Award from Melanoma Research Alliance and Pfizer, Inc., NIH R01 CA182635, and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (A.E. Aplin). SKCC Flow Cytometry and Translational Pathology core facilities are supported by NIH/NCI Support Grant (P30 CA056036). The RPPA Core Facility at MD Anderson Cancer Center is supported by a NCI Cancer Center Support Grant (CA16672). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/9/15
Y1 - 2016/9/15
N2 - Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma.
AB - Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma.
UR - http://www.scopus.com/inward/record.url?scp=84988946989&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84988946989&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-3384
DO - 10.1158/0008-5472.CAN-15-3384
M3 - Article
C2 - 27488531
AN - SCOPUS:84988946989
SN - 0008-5472
VL - 76
SP - 5455
EP - 5466
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -