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.

Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions

“…S7). Similar results have been reported previously for cotreatment experiments with carboplatin and palbociclib (65). Of note, the dosing regimen is expected to have a critical role in avoiding potential antagonistic effects.…”

Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma

“…In addition, this stratification could be used to determine novel second-line treatment options such as CDK4 inhibition (which inhibits the interaction with cyclin D1 resulting in hypophosphorylation of RB1 and E2F inactivation). 15 Konecny et al reported that ovarian cancer cell lines with RB1 deletions and CCNE1 gains are more resistant to CDK4 inhibitors, whereas those with CDKN2A gene deletions and decreased protein expression were more sensitive. 15 We found that CDKN2A and/or CDK4 gene deletions are rare in high-grade serous carcinoma and that cyclin D1 overexpression is predominant in the p16 hetero/ RB1 þ tumors.…”

“…15 Konecny et al reported that ovarian cancer cell lines with RB1 deletions and CCNE1 gains are more resistant to CDK4 inhibitors, whereas those with CDKN2A gene deletions and decreased protein expression were more sensitive. 15 We found that CDKN2A and/or CDK4 gene deletions are rare in high-grade serous carcinoma and that cyclin D1 overexpression is predominant in the p16 hetero/ RB1 þ tumors. Patients within the p16 hetero/ RB1 þ subgroup may be predicted to benefit most from CDK4 inhibitor treatments, in contrast to patients with cyclin E1 gains/amplifications in the p16 homo/RB1 þ subgroup and RB1 deletions in the p16 homo/RB1 À subgroup.…”

“…13,14 Similarly, elevated p16 occurs in 70% of high-grade serous carcinoma, but the RB1 mutation rate is low (4-6%) and only 6% of cases have protein loss. 5,15 Furthermore, the correlation between RB1 and p16 protein expression in highgrade serous carcinoma has not yet been explored in depth and associations between different retinoblastoma pathway alterations and clinical outcome/ treatment response remain poorly investigated. In this study, we identify non-synonymous retinoblastoma pathway deregulation modalities that stratify patients with different responses to firstline platinum-based chemotherapy.…”

Targeting CDK6 in cancer: State of the art and new insights

“…This cellular effectiveness has also been reflected in various tumor xenograft models. [95][96][97][98][99][100][101][102] Currently, in its phase III clinical trial, PD0332991 is being tested in patients with squamous cell lung cancer and has been granted accelerated approval for use in combination with letrozole for the treatment of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR C /HER2 ¡ ) breast cancer in postmenopausal women for their metastatic disease (http://www.fda.gov/). Despite the exciting therapeutic outcomes obtained from this combination therapy and its advantage in combating drug resistance, there should be a certain degree of caution when considering combination regimens.…”