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


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Authors

Tolcher, Anthony W 
Khan, Khurum 
Ong, Michael 
Banerji, Udai 
Papadimitrakopoulou, Vassiliki 

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/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).

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Keywords

Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Cell Line, Tumor, Female, Heterocyclic Compounds, 3-Ring, Humans, MAP Kinase Kinase Kinases, Male, Mice, Middle Aged, Neoplasms, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins p21(ras), Xenograft Model Antitumor Assays, ras Proteins

Journal Title

Clin Cancer Res

Conference Name

Journal ISSN

1078-0432
1557-3265

Volume Title

21

Publisher

American Association for Cancer Research (AACR)
Sponsorship
The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK (grant number: C347/A18077). Support was also provided by an Experimental Cancer Medicine Centre grant (no grant number) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research) (grant numbers: A46/CCR - CCR4057 & CCR4058).