PI3K/mTOR inhibition potentiates and extends palbociclib activity in anaplastic thyroid cancer

Kristen Wong, Francesca Di Cristofano, Michela Ranieri, Daniela De Martino, Antonio Di Cristofano

Research output: Contribution to journalArticle

Abstract

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite its low incidence, it accounts for a disproportionate number of thyroid cancer-related deaths, because of its resistance to current therapeutic approaches. Novel actionable targets are urgently needed to prolong patient survival and increase their quality of life. Loss and mutation of the RB1 tumor suppressor are rare events in ATC, which suggests that therapies directed at inhibiting the cyclin D/CDK4 complexes, responsible for RB phosphorylation and inactivation, might be effective in this tumor type. In fact, we found that the CDK4/6 inhibitor, palbociclib, strongly inhibits proliferation in all the RB1 wild-type ATC cell lines tested. Efficacy was also observed in vivo, in a xenograft model. However, ATC cells rapidly developed resistance to palbociclib. Resistance was associated with increased levels of cyclin D1 and D3. To counter cyclin D overexpression, we tested the effect of combining palbociclib with the PI3K/mTOR dual inhibitor, omipalisib. Combined treatment synergistically reduced cell proliferation, even in cell lines that do not carry PI3K-activating mutations. More importantly, low-dose combination was dramatically effective in inhibiting tumor growth in a xenograft model. Thus, combined PI3K/mTOR and CDK4/6 inhibition is a highly promising novel approach for the treatment of aggressive, therapy-resistant thyroid cancer.

Original languageEnglish (US)
Pages (from-to)425-436
Number of pages12
JournalEndocrine-Related Cancer
Volume26
Issue number4
DOIs
StatePublished - Jan 1 2018

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Phosphatidylinositol 3-Kinases
Thyroid Neoplasms
Cyclin D
Heterografts
Cyclin D3
Therapeutics
Cell Line
Neoplasms
Mutation
Cyclin D1
Phosphorylation
Quality of Life
Cell Proliferation
palbociclib
Anaplastic Thyroid Carcinoma
Survival
Incidence
Growth

Keywords

  • CDK4
  • MTOR
  • PI3K
  • RB
  • Thyroid cancer

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

Cite this

PI3K/mTOR inhibition potentiates and extends palbociclib activity in anaplastic thyroid cancer. / Wong, Kristen; Di Cristofano, Francesca; Ranieri, Michela; De Martino, Daniela; Di Cristofano, Antonio.

In: Endocrine-Related Cancer, Vol. 26, No. 4, 01.01.2018, p. 425-436.

Research output: Contribution to journalArticle

Wong, Kristen ; Di Cristofano, Francesca ; Ranieri, Michela ; De Martino, Daniela ; Di Cristofano, Antonio. / PI3K/mTOR inhibition potentiates and extends palbociclib activity in anaplastic thyroid cancer. In: Endocrine-Related Cancer. 2018 ; Vol. 26, No. 4. pp. 425-436.
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