Combining a GSI and BCL-2 inhibitor to overcome melanoma's resistance to current treatments.
Major limitations of current melanoma treatments are for instances of relapse and the lack of therapeutic options for BRAF wild-type patients who do not respond to immunotherapy. Many studies therefore focus on killing resistant subpopulations, such as Melanoma Initiating Cells (MICs) to prevent relapse. Here we examined whether combining a GSI (γ-Secretase Inhibitor) with ABT-737 (a small molecule BCL-2/BCL-XL/BCL-W inhibitor) can kill both the non-MICs (bulk of melanoma) and MICs. To address the limitations of melanoma therapies, we included multiple tumor samples of patients relapsed from current treatments, with a diverse genetic background (with or without the common BRAF, NRAS or NF1 mutations) in these studies. Excitingly, the combination treatment reduced cell viability and induced apoptosis of the non-MICs; disrupted primary spheres, decreased the ALDH+ cells, and inhibited the self-renewability of the MICs in multiple melanoma cell lines and relapsed patient samples. Using a low-cell-number mouse xenograft model, we demonstrated that the combination significantly reduced the tumor initiating ability of MIC-enriched cultures from relapsed patient samples. Mechanistic studies also indicate that cell death is NOXA-dependent. In summary, this combination may be a promising strategy to address treatment relapse and for triple wild-type patients who do not respond to immunotherapy.
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Nabanita
N
Mukherjee
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Adam
A
Almeida
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Katie A
KA
Partyka
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Yan
Y
Lu
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Josianna V
JV
Schwan
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Karoline
K
Lambert
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Madison
M
Rogers
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA.
William A
WA
Robinson
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA.
Steven E
SE
Robinson
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA.
Allison J
AJ
Applegate
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO 80045, USA.
Carol M
CM
Amato
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Yuchun
Y
Luo
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Mayumi
M
Fujita
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.|Department of Veterans Affairs Medical Center, Dermatology Section, Denver, CO 80220, USA.
David A
DA
Norris
University of Colorado Anschutz Medical Campus, School of Medicine, Department of Dermatology, Aurora, CO 80045, USA.
Yiqun G
YG
Shellman
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D025542:Neurofibromin 1 / Q000235:genetics; D009596:Nitrophenols / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C501332:ABT-737; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D025542:Neurofibromin 1; D009596:Nitrophenols; D009842:Oligopeptides; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D053829:Amyloid Precursor Protein Secretases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
ABT-737; BRAF-WT melanoma; GSI-I; melanoma initiating cells; melanoma stem cells