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

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.

SUBMITTER: Wong K

PROVIDER: S-EPMC6602869 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Wong Kristen K Di Cristofano Francesca F Ranieri Michela M De Martino Daniela D Di Cristofano Antonio A

Endocrine-related cancer 20190101 4

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 comp ...[more]

PMID: 30699064

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Project description:BackgroundIntrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer that is challenging to diagnose at an early stage. Despite recent advances in combination chemotherapy, drug resistance limits the therapeutic value of this regimen. iCCA reportedly harbors high HMGA1 expression and pathway alterations, especially hyperactivation of the CCND1/CDK4/CDK6 and PI3K signaling pathway. In this study, we explored the potential of targeting CDK4/6 and PI3K inhibition to treat iCCA.MethodsThe significance of HMGA1 in iCCA was investigated with in vitro/vivo experiments. Western blot, qPCR, dual-luciferase reporter and immunofluorescence assays were performed to examine the mechanism of HMGA1 induced CCND1 expression. CCK-8, western blot, transwell, 3D sphere formation and colony formation assays were conducted to predict the potential role of CDK4/6 inhibitors PI3K/mTOR inhibitors in iCCA treatment. Xenograft mouse models were also used to determine the efficacy of combination treatment strategies related to HMGA1 in iCCA.ResultsHMGA1 promoted the proliferation, epithelial-mesenchymaltransition (EMT), metastasis and stemness of iCCA. In vitro studies showed that HMGA1 induced CCND1 expression via promoting CCND1 transcription and activating the PI3K signaling pathway. Palbociclib(CDK4/6 inhibitor) could suppress iCCA proliferation, migration and invasion, especially during the first 3 days. Although there was more stable attenuation of growth in the HIBEpic model, we observed substantial outgrowth in each hepatobiliary cancer cell model. PF-04691502(PI3K/mTOR inhibitor) exhibited similar effects to palbociclib. Compared with monotherapy, the combination retained effective inhibition for iCCA through the more potent and steady inhibition of CCND1, CDK4/6 and PI3K pathway. Furthermore, more significant inhibition of the common downstream signaling pathways is observed with the combination compared to monotherapy.ConclusionsOur study reveals the potential therapeutic role of dual inhibition of CDK4/6 and PI3K/mTOR pathways in iCCA, and proposes a new paradigm for the clinical treatment of iCCA.

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

Publications

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

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