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Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

AbstractPURPOSE:
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/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined 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).
AuthorsAnthony 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 Papadopoulos, Victor Moreno, Brianne Kaiser, Timothy A Yap, Li Yan, Johann S de Bono
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 4 Pg. 739-48 (Feb 15 2015) ISSN: 1557-3265 [Electronic] United States
PMID25516890 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • AZD 6244
  • Benzimidazoles
  • Heterocyclic Compounds, 3-Ring
  • KRAS protein, human
  • MK 2206
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
  • Benzimidazoles (administration & dosage, adverse effects)
  • Cell Line, Tumor
  • Female
  • Heterocyclic Compounds, 3-Ring (administration & dosage, adverse effects)
  • Humans
  • MAP Kinase Kinase Kinases (antagonists & inhibitors)
  • Male
  • Mice
  • Middle Aged
  • Neoplasms (drug therapy, enzymology, genetics)
  • Proto-Oncogene Proteins (genetics)
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
  • Proto-Oncogene Proteins p21(ras)
  • Xenograft Model Antitumor Assays
  • ras Proteins (genetics)

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