Antitumor activity in ras-driven tumors by blocking akt and mek

Anthony W. Tolcher, Khurum Khan, Michael Ong, Udai Banerji, Vassiliki Papadimitrakopoulou, David R Gandara, Amita Patnaik, Richard D. Baird, David Olmos, Christopher R. Garrett, Jeffrey M. Skolnik, Eric H. Rubin, Paul D. Smith, Pearl Huang, Maria Learoyd, Keith A. Shannon, Anne Morosky, Ernestina Tetteh, Ying Ming Jou, Kyriakos P. PapadopoulosVictor Moreno, Brianne Kaiser, Timothy A. Yap, Li Yan, Johann S. De Bono

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedulefinding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were de fi ned as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS -mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS -driven human malignancies (Trial NCT number NCT01021748).

Original languageEnglish (US)
Pages (from-to)739-748
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number4
DOIs
StatePublished - Feb 15 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Tolcher, A. W., Khan, K., Ong, M., Banerji, U., Papadimitrakopoulou, V., Gandara, D. R., Patnaik, A., Baird, R. D., Olmos, D., Garrett, C. R., Skolnik, J. M., Rubin, E. H., Smith, P. D., Huang, P., Learoyd, M., Shannon, K. A., Morosky, A., Tetteh, E., Jou, Y. M., ... De Bono, J. S. (2015). Antitumor activity in ras-driven tumors by blocking akt and mek. Clinical Cancer Research, 21(4), 739-748. https://doi.org/10.1158/1078-0432.CCR-14-1901