Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines.
We have investigated the potential for the p16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three-quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma-specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16(INK) (4A) ) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance.
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.
Richard J
RJ
Young
Kelly
K
Waldeck
Claire
C
Martin
Jung H
JH
Foo
Donald P
DP
Cameron
Laura
L
Kirby
Hongdo
H
Do
Catherine
C
Mitchell
Carleen
C
Cullinane
Wendy
W
Liu
Stephen B
SB
Fox
Ken
K
Dutton-Regester
Nicholas K
NK
Hayward
Nicholas
N
Jene
Alexander
A
Dobrovic
Richard B
RB
Pearson
James G
JG
Christensen
Sophia
S
Randolph
Grant A
GA
McArthur
Karen E
KE
Sheppard
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
CDK4; CDKN2A; Cyclin D1; PD0332991; RB1; melanoma; p16INK4A