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

Anthony W Tolcher1, Khurum Khan2, Michael Ong2

  • 1South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio Texas.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|December 18, 2014
PubMed
Abstract

Insights

Combining MEK and AKT inhibitors shows promise for treating KRAS-mutant cancers, offering durable responses in patients with advanced solid tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS mutations are prevalent in human cancers.
  • KRAS-mutant tumors can resist MEK1/2 and AKT inhibitors individually.
  • Combined MEK and AKT inhibition may overcome resistance to monotherapies.

Purpose of the Study:

  • To evaluate the safety and efficacy of combining selumetinib (MEK1/2 inhibitor) and MK-2206 (AKT inhibitor) in patients with advanced solid tumors.
  • To determine optimal dosing and scheduling for the combination therapy.

Main Methods:

  • A dose/schedule-finding study was conducted.
  • Patients with advanced, treatment-refractory solid tumors were enrolled.
  • Recommended doses: MK-2206 135 mg weekly and selumetinib 100 mg daily.

Main Results:

  • The most common dose-limiting toxicity was grade 3 rash.
  • Other toxicities included lipase increase, stomatitis, diarrhea, fatigue, and retinal pigment epithelium detachment.
  • Partial responses were observed in non-small cell lung cancer and low-grade ovarian carcinoma.

Conclusions:

  • The combination of MEK and AKT inhibitors demonstrated clinical antitumor activity.
  • Responses in KRAS-mutant cancers were generally durable.
  • Cotargeting MEK and AKT signaling is a potential therapeutic strategy for KRAS-driven malignancies.

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