Melanoma is a major form of skin cancer and arises from the malignant transformation of melanocytes. One of the most commonly mutated genes in melanoma is B-RAF (~50%), which encodes a member of the RAF protein kinase family and an intermediate in the RAS-RAF-MEK-ERK signaling cascade. Findings from recent clinical trials using B-RAF inhibitors in malignant melanoma have shown great promise for B-RAF-targeted therapy. However, the clinical findings also revealed development of resistance to B-RAF inhibitor as a major therapeutic challenge. We have recently discovered a novel bi-directional crosstalk between B-RAF and the tumor suppressor LKB1-AMPK pathway, another important signaling pathway involved in the regulation of cancer cell growth, proliferation and survival. Activators of the LKB1-AMPK pathway (such as metformin, a common anti-diabetes drug, and its analog phenformin) have recently shown anti-tumor activities in cell culture studies and mouse models. Based on our recent findings, we hypothesize that combination treatment of B- RAF inhibitors and AMPK activators will offer therapeutic advantages for the treatment of melanoma over the B-RAF inhibitor single agent therapy, and holds the potential for overcoming drug resistance to B-RAF inhibitors. The goal of this proposal is to define the biochemical mechanism underlying the attenuation of BRAF-MEK-ERK signaling by AMPK and to assess pre-clinically the therapeutic benefit of combining AMPK activators with B-RAF inhibitors for melanoma treatment.
In aim 1, we will further elucidate the biochemical mechanism underlying the regulation of ERK signaling by AMPK and study its role in the regulation of cell proliferation and survival in response to energy stress.
In aim 2, we will evaluate the combinatory effect of AMPK activators and B-RAF inhibitors on inhibiting tumor growth in xenografts of human melanoma cell lines and in a B-RAF-driven genetically engineered mouse model. Finally, in aim 3, we will investigate the role of the LKB1-AMPK signaling in defining both acquired and intrinsic resistance to B-RAF inhibitors in melanoma therapy and assess the potential of AMPK activators on delaying the emergence of resistance to B-RAF inhibitors.

Public Health Relevance

Melanoma is the fifth most common cancer in American men and the seventh in American women based on estimated new cases for 2010. B-RAF kinase is a major oncogenic driver and therapeutic target in malignant melanoma. Our preclinical studies to assess the benefits of combination therapy using B-RAF inhibitors together with AMPK activators will provide important rational basis to develop better targeted therapy of malignant melanoma. If our hypothesis is proven true, this novel rational combinatory strategy may lead to an improved melanoma treatment with better patient survival.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA166717-04
Application #
8657935
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
DeRan, Michael; Yang, Jiayi; Shen, Che-Hung et al. (2014) Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep 9:495-503
Shen, Che-Hung; Yuan, Ping; Perez-Lorenzo, Rolando et al. (2013) Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell 52:161-72
Yuan, Ping; Ito, Koichi; Perez-Lorenzo, Rolando et al. (2013) Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A 110:18226-31