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Published on: November 11, 2016
Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma
McKenna Q Glasheen1, Signe Caksa1, Amelia G Young1
1Department of Pharmacology, Physiology and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Abstract:
Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.
Insights
Cellular inhibitor of apoptosis protein 2 (cIAP2) enables drug tolerance in melanoma persister cells by reducing cell death. Targeting cIAP2 during minimal residual disease (MRD) delays acquired resistance to MAPK-targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Drug tolerance and minimal residual disease (MRD) precede acquired resistance to targeted cancer therapies.
- Mechanisms of persister cell survival under targeted therapy are under investigation, with vulnerabilities remaining unclear.
- SOX10-deficient melanoma cells exhibit drug tolerance, a critical factor in treatment failure.
Purpose of the Study:
- To identify vulnerabilities in drug-tolerant persister (DTP) melanoma cells.
- To investigate the role of cellular inhibitor of apoptosis protein 2 (cIAP2) in melanoma drug tolerance.
- To evaluate targeting cIAP2 as a strategy to overcome resistance to MAPK-targeted therapy.
Main Methods:
- Expression analysis of cIAP2 in SOX10-deficient DTP melanoma cells.
- Investigating the mechanism of cIAP2-mediated drug tolerance, including transcriptional regulation by JUND.
- Utilizing a patient-derived xenograft model to assess the efficacy of birinapant (cIAP1/2 inhibitor) in combination with BRAF and MEK inhibitors during the MRD phase.
Main Results:
- cIAP2 is highly expressed in SOX10-deficient DTP melanoma cells and sufficient to induce tolerance to MEK inhibitors by decreasing cell death.
- cIAP2 upregulation is regulated at the transcript level in SOX10-deficient cells, requiring the AP-1 complex protein JUND.
- Treatment with birinapant during MRD delays acquired resistance to combination BRAF and MEK inhibitor therapy in a preclinical melanoma model.
Conclusions:
- Upregulation of cIAP2 in SOX10-deficient melanoma subpopulations contributes to drug tolerance against MAPK-targeting agents.
- Targeting cIAP2 represents a novel therapeutic strategy to overcome MRD and prevent acquired resistance in melanoma.
- This study provides a rationale for clinical trials combining cIAP inhibitors with MAPK-targeted therapies.
