Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., Cooper, Z. A., Chapman, P. B., Solit, D. B., Ribas, A., Lo, R. S., Flaherty, K. T., Ogino, S., Wargo, J. A., Golub, T. R. Nature 487, 500–504.

Speaker: Wan-Ting Kuo (郭琬婷)                                 Time: 13:00~14:00, Nov. 28, 2012

Commentator: Dr. Pei-Jung Lu (呂佩融博士)             Place: Room 601

Abstract:

Targeted drugs play an important role in the treatment of cancer. However, the clinical response remains unsatisfactory. Furthermore, the mechanisms to render tumor cells resistant to treatment remain unclear. In this study, the authors proposed that the tumor micro-environment renders innate resistance to treatment. Tumor micro-environment is a complex system of many cell types, including endothelial cells and their precursors, pericytes, smooth-muscle cells, fibroblasts of various phenotypes [1]. Resistance can occur immediately to drug treatment (primary or innate resistance) or may develop over time following exposure to the drug (acquired resistance). In this study, the treatment of drug triggers melanoma to initiate resistant mechanisms within a few days. The authors screened 23 stromal cells for influencing the innate resistance of 45 cancer cell lines using 35 anticancer drugs and then identified the stroma-mediated innate resistance of BRAF-mutant melanoma to RAF inhibitor. In healthy melanocytes, BRAF is known as serine/threonine-protein kinase B-Raf. Moreover, RAF kinase phosphorylates MEK which is known as mitogen-activated proteinkinase (MAPKK). The activated MEK phosphorylates mitogen-activated protein kinase (MAPK). Finally, MAPK activates extracellular signal-regulated kinases (ERK) which affects cell division, differentiation, and secretion. However, melanoma with BRAF V600E mutation in which valinewas replaced with glutamic acid at residue 600 showed the resistance to RAF inhibitor. RAF inhibitor (PLX4032) selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts [2]. By proteomic analysis, the authors found thathepatocyte growth factor(HGF), which was secreted by stromal cells, resulted in the activation of MET(HGF receptor) and triggering pathways of MAPK and phosphatidylinositol-3-OH kinase (PI3K-Akt) to resist RAF inhibitors. MET encoded from proto-oncogene met is the HGF receptor and encodes tyrosine-kinase activity. Taken together, this study indicates that the interaction between tumors and their micro-environment can uncover the mechanism of drug resistance.

References:

1.        Albini, A., Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7, 139-147.

2.        Bollag, G., Hirth, P., Tsai, J., Zhang, J. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596-9.