Abstract Number: 18

Making stressed melanoma self-destruct

Meeting: 2015 Dermcoll

Session Information

Date: -

Session Title: Melanoma Symposium

Session Time: -

Introduction: Melanoma drug resistance is, in part, due
to tumour heterogeneity. We have demonstrated that
melanomas are composed of differentially cycling tumour
cells in a subcompartment-specific distribution. Further, we
have shown that treatment with endoplasmic reticulum
(ER) stress-inducing drugs, fenretinide (synthetic retinoid)
or bortezomib (Velcade®) induces cell cycle arrest and
apoptosis of metastatic melanoma cells.
This study investigates the effect of ER stress-inducing
agents on the dynamics of cell division and death of individual
melanoma cells within the complex tumour
microenvironment, and to develop combination strategies
that increase the efficacy of ER stress-inducing agents for
melanoma therapy.
Methods: Melanoma cells were grown as 3D spheroids
and implanted into a collagen matrix to mimic tumour
architecture and microenvironment. Cutting-edge technology
was applied for real-time cell cycle imaging
(FUCCI) and for ER-stress detection (F-XBP1ΔDBD-venus
Results: Bortezomib induced ER stress, delayed proliferation,
and combination with fenretinide increased apoptosisin 2D and 3D culture. Real-time cell cycle imaging revealed
that bortezomib induced both G1 and G2 cell cycle arrest,
but preferentially killed G2-phase cells. Consequently, pretreatment
with temozolomide or fenretinide, causing
G2-arrest, sensitised melanoma cells to bortezomib. In contrast,
pretreatment with MEK-inhibitors, causing G1-arrest,
inhibited bortezomib cytotoxicity in all melanoma cells, as
did selective BRAF-inhibitors in BRAF-mutant melanoma
Conclusion: Bortezomib combined with fenretinide or
temozolamide is a strategy worth exploring for the treatment
of BRAF-inhibitor insensitive or resistant melanoma.
Importantly, melanoma cells arrested in G1 are protected
from bortezomib cytotoxicity, which excludes MAPK
pathway inhibitors as combination partners.