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p27kip1 expression and phosphorylation dictate Palbociclib sensitivity in KRAS-mutated colorectal cancer

Gian Luca Rampioni Vinciguerra1,2, Alessandra Dall'Acqua1, Ilenia Segatto1

  • 1Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, Aviano, Italy.

Cell Death & Disease
|October 16, 2021
PubMed

Insights

In KRAS-mutated colorectal cancer, p27kip1 expression inversely correlates with response to CDK4/6 inhibitors like Palbociclib. Targeting p27kip1 and Src may overcome resistance, identifying patients for combination therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • KRAS mutations (RASMUT) in colorectal cancer limit treatment options and worsen patient prognosis.
  • CDK4/6 inhibitors are a promising strategy, but patient selection and resistance remain challenges.
  • p27kip1 is a cyclin-dependent kinase (CDK) inhibitor investigated for its role in CDK4/6 inhibitor response.

Purpose of the Study:

  • To investigate the role of p27kip1 in colorectal cancer response to the CDK4/6 inhibitor Palbociclib.
  • To identify mechanisms of resistance to Palbociclib in RASMUT colorectal cancer.
  • To explore p27kip1 as a potential biomarker for stratifying patients for CDK4/6 inhibitor therapy.

Main Methods:

  • In vitro and in vivo studies using colorectal cancer models.
  • Generation of Palbociclib-resistant RASMUT colorectal cancer cell lines.
  • Analysis of p27kip1 expression, protein interactions, and phosphorylation.
  • Evaluation of Src inhibitors in combination with Palbociclib.

Main Results:

  • p27kip1 expression inversely correlated with Palbociclib response in colorectal cancer.
  • Palbociclib-resistant cells exhibited increased p27kip1, cyclin D, CDK4, and CDK6 expression.
  • Increased Src-mediated p27kip1 phosphorylation was observed in resistant cells.
  • Src inhibitors re-sensitized resistant cells to Palbociclib.

Conclusions:

  • p27kip1 expression may predict response to Palbociclib in RASMUT colorectal cancer.
  • Src-mediated phosphorylation of p27kip1 contributes to Palbociclib resistance.
  • p27kip1 could serve as a biomarker for patient stratification in combination therapy with CDK4/6 and Src inhibitors.

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