Grp94-specific monoclonal antibody to counteract BRAF inhibitor resistance in BRAFV600E melanoma

F Sabbatino,X Wang,Cr Ferrone,Y Wang,E Favoino,S Ferrone,L Yang,V Villani,L Cai

doi:10.1186/1479-5876-13-s1-k12

Abstract

The development of BRAF-I resistance in BRAFV600E melanoma underlies the need to develop strategies to counteract this resistance. It has been shown that administration of heat shock protein 90 (HSP90) inhibitors can counteract multiple mechanisms which drive BRAF-I resistance by reactivation of MAPK and activation of PI3K/AKT pathway. However the clinical application of this strategy is hampered the high toxicity associated with administration of currently available HSP90 inhibitors. To overcome this limitation we have developed a novel monoclonal antibody (mAb), named W9, which recognizes an extracellular epitope of glucose regulated protein of 94 kDa (Grp94), a member of the HSP90 family. The mAb W9 defined Grp94-epitope is selectively expressed on malignant cells but is not detectable on normal cells. Therefore targeting Grp94-epitope by mAb W9 is expected to cause limited if any side effects. The mAb W9 was found to increase and restore the sensitivity to BRAF-I of BRAFV600E melanoma cells including cells which have acquired BRAF-I resistance because of PDGFRα upregulation.

Highlights

Convenient online submission Thorough peer review No space constraints or color figure charges Immediate publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Research which is freely available for redistribution
It has been shown that administration of heat shock protein 90 (HSP90) inhibitors can counteract multiple mechanisms which drive BRAF-I resistance by reactivation of MAPK and activation of PI3K/AKT pathway
The clinical application of this strategy is hampered the high toxicity associated with administration of currently available HSP90 inhibitors

Summary

Introduction

Grp94-specific monoclonal antibody to counteract BRAF inhibitor resistance in BRAFV600E melanoma F Sabbatino, E Favoino, Y Wang, X Wang, V Villani, L Cai, L Yang, S Ferrone*, CR Ferrone From Melanoma Bridge Meeting 2014 Naples, Italy.

Results

Conclusion