2. Academic Validation
  3. Expression Differences in BCL2 Family Members between Uveal and Cutaneous Melanomas Account for Varying Sensitivity to BH3 Mimetics

Expression Differences in BCL2 Family Members between Uveal and Cutaneous Melanomas Account for Varying Sensitivity to BH3 Mimetics

  • J Invest Dermatol. 2022 Jul;142(7):1912-1922.e7. doi: 10.1016/j.jid.2021.11.035.
Nabanita Mukherjee 1,  Chiara R Dart 2,  Carol M Amato 3,  Adam Honig-Frand 3,  James R Lambert 4,  Karoline A Lambert 1,  William A Robinson 3,  Richard P Tobin 5,  Martin D McCarter 5,  Kasey L Couts 3,  Mayumi Fujita 6,  David A Norris 7,  Yiqun G Shellman 8
Affiliations

Affiliations

  • 1 Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 2 Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 3 Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 4 Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 5 Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
  • 6 Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Dermatology Section, U.S. Department of Veterans Affairs Medical Center, Denver, Colorado, USA; Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 7 Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Dermatology Section, U.S. Department of Veterans Affairs Medical Center, Denver, Colorado, USA.
  • 8 Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address: Yiqun.Shellman@cuanschutz.edu.
PMID: 34942200 DOI: 10.1016/j.jid.2021.11.035
Abstract

Uveal melanoma (UM) is a subtype of melanoma. Although they share a melanocytic origin with cutaneous melanoma (CM), patients with UM have few treatment options. BCL2 homologous 3 mimetics are small-molecule drugs that mimic proapoptotic BCL2 family members. We compared BCL2 family member expression between UM and CM using immunoblot and The Cancer Genome Atlas transcriptomic analysis. UM has a unique signature of low BFL1 and high PUMA proteins compared with CM and 30 other Cancer types, making them an attractive candidate for BCL2 homologous 3 protein mimetics. We tested the efficacy of a BCL2 inhibitor and MCL1 inhibitor (MCL1i) in UM, with viability assays, live-cell imaging, sphere assays, and mouse xenograft models. UM had a higher sensitivity to MCL1i than CM. Overexpression of BFL1 or knockdown of PUMA made the UM more resistant to MCL1i. In contrast, MAPK/extracellular signal‒regulated kinase inhibitor treatment in CM made them more sensitive to MCL1i. However, MCL1i-alone treatment was not very effective to reduce the UM initiating cells; to overcome this, we employed a combination of MCL1i with BCL2 inhibitor that synergistically inhibited UM initiating cell's capacity to expand. Overall, we identify a distinct expression profile of BCL2 family members for UM that makes them susceptible to BCL2 homologous 3 mimetics.

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