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293 Molecular determinants of CDK4 inhibitor activity in low-grade serous ovarian cancer
  1. M Llaurado Fernandez1,
  2. J Hoenisch1,
  3. H Kim1,
  4. A Dawson1,
  5. N Lam1,
  6. D Cheasley2,
  7. K Gorrienge2,
  8. N Abhimanyu2,
  9. I Campbell2,
  10. D Huntsman3,
  11. G DiMattia4,
  12. M Kobel5 and
  13. M Carey1
  1. 1University of British Columbia, Obstetrics and Gynaecology, Vancouver, Canada
  2. 2Peter MacCallum Cancer Centre, Cancer Genetics and Genomics, Melbourne, Australia
  3. 3British Columbia Cancer Research Center, Molecular Oncology, Vancouver, Canada
  4. 4University of Western Ontario, Oncology, London, Canada
  5. 5University of Calgary, Pathology and Laboratory Medicine, Calgary, Canada


Objectives Effective therapies for low-grade serous ovarian cancer (LGSC) patients are urgently needed. CDKN2A/B (p16) loss and hormone receptor (ER/PR) expression are well described in LGSC. We aimed to study p16-CDK4-Rb pathway status and CDK4/6 inhibitior (CDK4/6i) activity in LGSC cell lines.

Methods Protein expression of p16, CDK4, CDK6, Rb, p-Rb, CCDN1 and E2F were evaluated by western blot in 13 LGSC and 2 breast cancer (BCa) lines. Gene mutation and copy-number (CN) data on the selected candidates were obtained using whole-exome sequencing (WES) analyses. CN data on 93 LGSC FFPE tumors was also obtained. Palbociclib (CDK4/6i) effects were evaluated using IC50 assays.

Results None of the LGSC lines had detectable mutations in p16, CDK4, CDK6, Rb, p-Rb, CCDN1 or E2F genes. CDK4/CDK6 protein expression was present in all lines. Absence of p16 protein expression and CDKN2A CN loss was detected in 84.6% (11/13) LGSC cell lines. Interestingly, total and phosphorylated Rb were detected in both BCa lines, but only in 53.8% (7/13) LGSC lines. RB1 hemizygous CN loss was detected in 7.7% (1/13) LGSC lines and in 7.5% (7/93) LGSC tumors. Palbociclib had limited cytotoxic effects in the BCa and LGSC cell lines tested.

Conclusions Palbociclib mainly has cytostatic effects in LGSC in-vitro and its activity does not correlate with either p16 or CDK4 expression. About half of our cell lines showed Rb loss, likely mediated by post-translational events. Rb-proficiency is required for drug efficacy in other cancers, and may account for our observations. These results raise important considerations for clinical trial design.

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