MEK1/2 Inhibitor Increases Therapeutic Response in Combination With Radiation: Presented at AACR-NCI-EORTC

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Title: MEK1/2 Inhibitor Increases Therapeutic Response in Combination With Radiation: Presented at AACR-NCI-EORTC
URL: http://www.pslgroup.com/dg/216526.htm
Doctor's Guide
October 26, 2007

By Crina Frincu-Mallos, PhD

SAN FRANCISCO, CA -- October 26, 2007 -- The Ras/Rat/MEK/ERK signalling pathway is activated in most human tumours as a result of abnormal signalling from upstream proteins MEK1/2 or Ras and Raf. The consequence of this activation is an increase in cell proliferation and enhanced cell survival.

Currently the only known activator of ERK, MEK1/2, is an interesting target for cancer therapeutics, especially due to its key position downstream of the oncogenes Ras and Raf.

Combining a small molecule inhibitor developed by AstraZeneca, AZD6244, with radiation therapy resulted in a synergistic effect when looking at the inhibition of MEK1/2 in a human lung tumour xenograft model.

Researchers reported the findings here at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on October 23.

AZD6244 (also known as ARY-142886) is a selective, potent, uncompetitive, tight-binding inhibitor of MEK1/2 that has shown high activity in both in vitro and in vivo tumour models, and in phase 2 clinical trials, said study presenter Aoife M. Shannon, PhD, postdoctoral fellow, University of Manchester, on behalf of her colleagues at University of Manchester and AstraZeneca, United Kingdom.

Dr. Shannon and colleagues assessed the therapeutic effects of the combination and evaluated the impact of MEK1/2 inhibition on responses to hypoxia at the molecular level, using Calu-6 (a KRAS mutant).

In vivo pharmacodynamic studies were performed in Calu-6 DC xenografts with AZD6244 25 mg/kg BID, given orally at 8-hours intervals. Tumours were harvested 4 hours after one dose of AZD6244 or after 5 days of treatment.

Subsequently, a 10-day treatment with AZD6244 25 mg/kg BID was given in combination with irradiation (5 x 2 Gy) during the first or last 5 days of drug therapy. In the combination groups, AZD6244 was administered 2 hours prior and 6 hours after each radiation dose. Tumours were harvested after reaching three times the correspondent pretreatment tumour volume (RTV3).

The researchers used Western blot analysis to look at the effect of AZD6244 and radiation therapy in combination on the phospho-ERK biomarker, as well as on HIF-1alpha, under hypoxic conditions (1% O₂).

Clonogenic assays were used to determine the optimal scheduling of AZD6244, i.e., before, after, or simultaneously with radiotherapy. Cells were treated for 48 hours with two doses of AZD6244 (20 nM or 200 nM) before irradiation (2, 4, or 6 Gy).

In concentrations higher than 2 nM, AZD6244 reduced the level of activated phospho-ERK, while radiation therapy seemed to have no effect on ERK activation in vitro, said Dr. Shannon.

Clonogenic assays show that the combination is optimal when AZD6244 is used the in neoadjuvant setting (ie, 48 hours before irradiation, noted Dr. Shannon.

Regarding the effect of AZD6244 on HIF transactivation in vitro, Western blotting analyses show that 20 nM, 200nM, and 2000 nM of AZD6244 reduced HIF-1 protein expression by 16.7%, 32.6%, and 52.4%, respectively.

The 10-day treatment with AZD6244 enhanced the radiotherapy response of tumour xenografts, regardless of whether the radiation was administered during the first or the last 5 days of the cycle. Calu-6 xenografts exhibited tumour regression after dosing with AZD6244, said Dr. Shannon and colleagues.

When compared with controls, both AZD6244 and radiation therapy as monotherapies increased the time to RTV3. However, AZD6244 and radiation in combination resulted in a significant increase in the time to RTV3, compared with controls (40 days vs 15 days, P <.05), the researchers said.

"The MEK proteins are part of the pathway that controls the production of HIF-1, the hypoxia-related protein involved in stabilising cells in the absence of oxygen," said Dr. Shannon. "Furthermore, HIF is associated with protecting tumours from the effects of radiation."

"It is possible that the effect of AZD6244 on HIF as well as tumour blood vessel growth induced by HIF contributed towards the remarkable effects of the combination," Dr. Shannon said. "It is a double-pronged approach that will likely be relevant to ongoing trials of MEK inhibitors and inform future studies."

Funding for this study was provided by AstraZeneca, Alderley Park, Macclesfield, United Kingdom.

[Presentation title: AZD6244 (ARRY-142886), a Potent and Highly Selective MEK1/2 Inhibitor, Demonstrates Anti-HIF Properties, and Increases The Therapeutic Response in a Lung Tumour Xenograft Model When Combined With Radiotherapy. Abstract A244]

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