Antitumor Activity in RAS-Driven Tumors by Blocking AKT and MEK

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

来源：Clinical Cancer Research, 2015, 21(4): 739-748.

DOI：10.1158/1078-0432.CCR-14-1901

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/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.

• 出版日期2015-2-15