Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK
Tolcher, Anthony W
Garrett, Christopher R
Skolnik, Jeffrey M
Papadopoulos, Kyriakos P
Yap, Timothy A
de, Bono Johann S
Clinical Cancer Research
American Association for Cancer Research
MetadataShow full item record
Tolcher, A. W., Khan, K., Ong, M., Banerji, U., Papadimitrakopoulou, V., Gandara, D., Patnaik, A., et al. (2014). Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK. Clinical Cancer Research, 21 https://doi.org/10.1158/1078-0432.CCR-14-1901
Purpose: KRAS is the most commonly mutated oncogene in human tumours. 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 tumours. Recommended dosing schedules were defined as MK-2206 135 mg weekly and selumetinib 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, diarrhoea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical anti-tumour 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 co-targeting of MEK and AKT signalling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748).
Phase I Trial, RAS, MEK, AKT, Combination
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).
External DOI: https://doi.org/10.1158/1078-0432.CCR-14-1901
This record's URL: http://www.repository.cam.ac.uk/handle/1810/246941