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
  • 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: [email protected].
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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