June 9 2017
We had a large number of participants come to the 25th IRCMS Seminar held on June 9, for which we would like to express our gratitude.
Date: June 9, 2017 (Fri) Time: 16:00 - 17:00
Venue: 2F Seminar Room, Center for AIDS Research (CAIDS)
Speaker: Eishu Hirata, M.D.,Ph.D.
Senior Assistant Professor, Department of Oncologic Pathology, Kanazawa Medical University
"Imaging 'Failure' How BRAF inhibition generates drug tolerant microenvironments"
Intravital imaging of BRAF-mutant melanoma cells containing an ERK/MAPK biosensor reveals how the tumor microenvironment affects response to BRAF inhibition by PLX4720. Initially, melanoma cells respond to PLX4720, but rapid reactivation of ERK/MAPK is observed in areas of high stromal density. This is linked to ''paradoxical'' activation of melanoma-associated fibroblasts by PLX4720 and the promotion of matrix production and remodeling leading to elevated integrin β1/FAK/Src signaling in melanoma cells. Fibronectin-rich matrices with 3-12 kPa elastic modulus are sufficient to provide PLX4720 tolerance. Co-inhibition of BRAF and FAK abolished ERK reactivation and led to more effective control of BRAF-mutant melanoma. We propose that paradoxically activated MAFs provide a ''safe haven'' for melanoma cells to tolerate BRAF inhibition.