Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy

Clara Albanese, Rachele Alzani, Nadia Amboldi, Nilla Avanzi, Dario Ballinari, Maria Gabriella Brasca, Claudio Festuccia, Francesco Fiorentini, Giuseppe Locatelli, Wilma Pastori, Veronica Patton, Fulvia Roletto, Francesco Colotta, Arturo Galvani, Antonella Isacchi, Jurgen Moll, Enrico Pesenti, Ciro Mercurio, Marina Ciomei

Research output: Contribution to journalArticle

Abstract

Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC50. PHA-848125-treated cells show cell cycle arrest in G1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment.

Original languageEnglish
Pages (from-to)2243-2254
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Albanese, C., Alzani, R., Amboldi, N., Avanzi, N., Ballinari, D., Brasca, M. G., Festuccia, C., Fiorentini, F., Locatelli, G., Pastori, W., Patton, V., Roletto, F., Colotta, F., Galvani, A., Isacchi, A., Moll, J., Pesenti, E., Mercurio, C., & Ciomei, M. (2010). Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Molecular Cancer Therapeutics, 9(8), 2243-2254. https://doi.org/10.1158/1535-7163.MCT-10-0190