Reference Detail

Ref Type

Journal Article

PMID

(27488531)

Authors

Teh JL, Purwin TJ, Greenawalt EJ, Chervoneva I, Goldberg A, Davies MA, Aplin AE

Title

An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	18	2016 Sep 15	5455-66	Cancer Res

URL

Abstract Text

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. Cancer Res; 76(18); 5455-66. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS mutant	melanoma	no benefit	PD-0325901	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PD-0325901 treatment resulted in stable tumor growth in melanoma cell line xenograft models harboring an NRAS mutation, however, growth later ensued and thus, demonstrates a lack of benefit (PMID: 27488531).	27488531
NRAS wild-type	melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, an NRAS wild-type melanoma cell line demonstrated inhibition of cell growth when treated with Mekinist (trametinib) in culture (PMID: 27488531).	27488531
BRAF mutant	melanoma	sensitive	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring a BRAF mutation demonstrated greater sensitivity to the combination treatment of Mekinist (trametinib) and Ibrance (palbociclib) in culture when compared to either agent alone (PMID: 27488531).	27488531
CDKN2A loss	melanoma	resistant	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line deficient for CDKN2A demonstrated resistance to treatment with Ibrance (palbociclib) in culture (PMID: 27488531).	27488531
BRAF V600E	melanoma	conflicting	PD-0325901	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a melanoma cell line xenograft model harboring BRAF V600E treated with PD-0325901 demonstrated stable tumor growth, but by day 44, growth ensued and thus, demonstrated no benefit (PMID: 27488531).	27488531
BRAF V600E	melanoma	sensitive	Palbociclib + PD-0325901	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination treatment of PD-0325901 and Ibrance (palbociclib) resulted in significant tumor regression in melanoma cell line xenograft models harboring BRAF V600E and demonstrated a 56% (5/9) complete response rate (PMID: 27488531).	27488531
BRAF mut RB1 loss	melanoma	decreased response	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring a BRAF mutation and RB1 loss demonstrated reduced sensitivity when treated with Mekinist (trametinib) in culture (PMID: 27488531).	27488531
NRAS mutant	melanoma	conflicting	Palbociclib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Ibrance (palbociclib) treatment resulted in stable tumor growth in melanoma cell line xenograft models harboring an NRAS mutation, however, growth later ensued and thus, demonstrated a lack of benefit (PMID: 27488531).	27488531
NRAS mutant	melanoma	sensitive	Palbociclib + PD-0325901	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination treatment of PD-0325901 and Ibrance (palbociclib) resulted in tumor regression in 33% (2/6) of melanoma xenograft models harboring an NRAS mutation (PMID: 27488531).	27488531
NRAS wild-type	melanoma	decreased response	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, an NRAS wild-type melanoma cell line demonstrated minimal sensitivity when treated with the combination of Ibrance (palbociclib) and Mekinist (trametinib) in culture (PMID: 27488531).	27488531
CDKN2A loss	melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line with CDKN2A loss demonstrated sensitivity to Mekinist (trametinib) in culture, resulting in inhibition of cell growth (PMID: 27488531).	27488531
BRAF wild-type	melanoma	sensitive	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, BRAF wild-type melanoma cells demonstrated decreased cell viability when treated with Ibrance (palbociclib) in culture (PMID: 27488531).	27488531
NRAS wild-type	melanoma	sensitive	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, NRAS wild-type melanoma cells demonstrated decreased cell viability when treated with Ibrance (palbociclib) in culture (PMID: 27488531).	27488531
BRAF wild-type	melanoma	decreased response	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a BRAF wild-type melanoma cell line demonstrated minimal sensitivity when treated with the combination of Ibrance (palbociclib) and Mekinist (trametinib) in culture (PMID: 27488531).	27488531
BRAF V600E	melanoma	no benefit	Palbociclib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with Ibrance (palbociclib) in a melanoma cell line xenograft model harboring BRAF V600E resulted in no benefit, demonstrating low but continuous growth (PMID: 27488531).	27488531
BRAF mut RB1 loss	melanoma	decreased response	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring a BRAF mutation and loss of RB1 demonstrated a decreased response to Ibrance (palbociclib) treatment in culture when compared to treatment of melanoma cell lines wild-type for BRAF (PMID: 27488531).	27488531
BRAF mut RB1 loss	melanoma	decreased response	Palbociclib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line with a BRAF mutation and loss of RB1 demonstrated minimal sensitivity when treated with the combination of Ibrance (palbociclib) and Mekinist (trametinib) in culture (PMID: 27488531).	27488531