CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models

Agnieszka K. Witkiewicz, Derek Cox, Erik S. Knudsen

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

In spite of the efficacy of Her2-targeted therapies, recurrence and progression remain a challenge for treatment of Her2 positive breast cancer. CDK4/6 function downstream of Her2; therefore, inhibition of these kinases could represent an important therapeutic approach to augment the effectiveness of standard therapies. In models of acquired resistance to Her2-targeted therapies, Cyclin D1 was inappropriately activated and CDK4/6 inhibition was effective at blocking proliferation by targeting this common pathway associated with resistance. These data were recapitulated in Her2 positive xenografts. Furthermore, in a series of 35 primary breast tumor explants, treatment with PD-0332991 resulted in a greater than 4-fold suppression of the Ki67. The effects of CDK4/6 inhibition were dependent on an intact RB-pathway, and consonantly, loss of RB and high-levels of p16 were associated with resistance to CDK4/6 inhibition. Combination studies illustrated that CDK4/6 inhibition is cooperative with multiple Her2-targeted agents and provides a complementary mechanism of action to T-DM1 to efficiently suppresses the proliferation of residual Her2-positive tumor cell populations that survive T-DM1. Together, these data indicate CDK4/6 is a viable therapeutic target that functions downstream of Her2, and tissue based markers are available to direct rational utilization of CDK4/6 inhibitors in combination with Her2-targeted agents.

Original languageEnglish (US)
Pages (from-to)261-272
Number of pages12
JournalGenes and Cancer
Volume5
Issue number7-8
StatePublished - 2014

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Breast Neoplasms
Therapeutics
Cyclin D1
Heterografts
Phosphotransferases
Recurrence
Population
Neoplasms

Keywords

  • CDK4
  • HER2
  • Palbocicllb
  • RB
  • T-DM1

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. / Witkiewicz, Agnieszka K.; Cox, Derek; Knudsen, Erik S.

In: Genes and Cancer, Vol. 5, No. 7-8, 2014, p. 261-272.

Research output: Contribution to journalArticle

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