Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer

Gottfried E. Konecny, Boris Winterhoff, Teodora Kolarova, Jingwei Qi, Kanthinh Manivong, Judy Dering, Guorong Yang, Meenal Chalukya, He Jing Wang, Lee Anderson, Kimberly R. Kalli, Richard S. Finn, Charles Ginther, Siân Jones, Victor E. Velculescu, Darren Riehle, William Arthur Cliby, Sophia Randolph, Maria Koehler, Lynn C. Hartmann & 1 others Dennis J. Slamon

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Purpose: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. Experimental Design: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. Results: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052). Conclusions: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.

Original languageEnglish (US)
Pages (from-to)1591-1602
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number6
DOIs
StatePublished - Mar 15 2011

Fingerprint

Retinoblastoma
Ovarian Neoplasms
Cell Line
Phosphorylation
G1 Phase Cell Cycle Checkpoints
Gene Expression Profiling
Pharmaceutical Preparations
Disease-Free Survival
Cell Cycle
Research Design
Phosphotransferases
Western Blotting
Immunohistochemistry
palbociclib
Apoptosis
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Konecny, G. E., Winterhoff, B., Kolarova, T., Qi, J., Manivong, K., Dering, J., ... Slamon, D. J. (2011). Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clinical Cancer Research, 17(6), 1591-1602. https://doi.org/10.1158/1078-0432.CCR-10-2307

Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. / Konecny, Gottfried E.; Winterhoff, Boris; Kolarova, Teodora; Qi, Jingwei; Manivong, Kanthinh; Dering, Judy; Yang, Guorong; Chalukya, Meenal; Wang, He Jing; Anderson, Lee; Kalli, Kimberly R.; Finn, Richard S.; Ginther, Charles; Jones, Siân; Velculescu, Victor E.; Riehle, Darren; Cliby, William Arthur; Randolph, Sophia; Koehler, Maria; Hartmann, Lynn C.; Slamon, Dennis J.

In: Clinical Cancer Research, Vol. 17, No. 6, 15.03.2011, p. 1591-1602.

Research output: Contribution to journalArticle

Konecny, GE, Winterhoff, B, Kolarova, T, Qi, J, Manivong, K, Dering, J, Yang, G, Chalukya, M, Wang, HJ, Anderson, L, Kalli, KR, Finn, RS, Ginther, C, Jones, S, Velculescu, VE, Riehle, D, Cliby, WA, Randolph, S, Koehler, M, Hartmann, LC & Slamon, DJ 2011, 'Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer', Clinical Cancer Research, vol. 17, no. 6, pp. 1591-1602. https://doi.org/10.1158/1078-0432.CCR-10-2307
Konecny, Gottfried E. ; Winterhoff, Boris ; Kolarova, Teodora ; Qi, Jingwei ; Manivong, Kanthinh ; Dering, Judy ; Yang, Guorong ; Chalukya, Meenal ; Wang, He Jing ; Anderson, Lee ; Kalli, Kimberly R. ; Finn, Richard S. ; Ginther, Charles ; Jones, Siân ; Velculescu, Victor E. ; Riehle, Darren ; Cliby, William Arthur ; Randolph, Sophia ; Koehler, Maria ; Hartmann, Lynn C. ; Slamon, Dennis J. / Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 6. pp. 1591-1602.
@article{78b776ca0ecd44fc8ef1a3e0d57a22ff,
title = "Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer",
abstract = "Purpose: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. Experimental Design: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. Results: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37{\%}) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95{\%} CI 1.00-2.24, P = 0.052). Conclusions: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.",
author = "Konecny, {Gottfried E.} and Boris Winterhoff and Teodora Kolarova and Jingwei Qi and Kanthinh Manivong and Judy Dering and Guorong Yang and Meenal Chalukya and Wang, {He Jing} and Lee Anderson and Kalli, {Kimberly R.} and Finn, {Richard S.} and Charles Ginther and Si{\^a}n Jones and Velculescu, {Victor E.} and Darren Riehle and Cliby, {William Arthur} and Sophia Randolph and Maria Koehler and Hartmann, {Lynn C.} and Slamon, {Dennis J.}",
year = "2011",
month = "3",
day = "15",
doi = "10.1158/1078-0432.CCR-10-2307",
language = "English (US)",
volume = "17",
pages = "1591--1602",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer

AU - Konecny, Gottfried E.

AU - Winterhoff, Boris

AU - Kolarova, Teodora

AU - Qi, Jingwei

AU - Manivong, Kanthinh

AU - Dering, Judy

AU - Yang, Guorong

AU - Chalukya, Meenal

AU - Wang, He Jing

AU - Anderson, Lee

AU - Kalli, Kimberly R.

AU - Finn, Richard S.

AU - Ginther, Charles

AU - Jones, Siân

AU - Velculescu, Victor E.

AU - Riehle, Darren

AU - Cliby, William Arthur

AU - Randolph, Sophia

AU - Koehler, Maria

AU - Hartmann, Lynn C.

AU - Slamon, Dennis J.

PY - 2011/3/15

Y1 - 2011/3/15

N2 - Purpose: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. Experimental Design: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. Results: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052). Conclusions: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.

AB - Purpose: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. Experimental Design: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. Results: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052). Conclusions: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.

UR - http://www.scopus.com/inward/record.url?scp=79952710710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952710710&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-10-2307

DO - 10.1158/1078-0432.CCR-10-2307

M3 - Article

VL - 17

SP - 1591

EP - 1602

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 6

ER -