Combined inhibition of cyclin-dependent kinases (dinaciclib) and AKT(MK-2206) blocks pancreatic tumor growth and metastases in patient-derived xenograft models

Chaoxin Hu, Tikva Dadon, Venugopal Chenna, Shinichi Yabuuchi, Rajat Bannerji, Robert Booher, Peter Strack, Nilofer Azad, Barry D. Nelkin, Anirban Maitra

Research output: Contribution to journalArticle

Abstract

KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5) reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patientderived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., three times a week) and MK-2206 (60 mg/kg, orally, three times a week) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI-CTEP-approved multicenter phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened.

Original languageEnglish (US)
Pages (from-to)1532-1539
Number of pages8
JournalMolecular cancer therapeutics
Volume14
Issue number7
DOIs
StatePublished - Jul 1 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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