Targeting the cyclin dependent kinase and retinoblastoma axis overcomes standard of care resistance in BRAFV600E-mutant melanoma

Antoneicka L. Harris, Samantha E. Lee, Louis K. Dawson, Laura A. Marlow, Brandy H. Edenfield, William F. Durham, Thomas J. Flotte, Michael Thompson, Daniel L. Small, Aidan J. Synnott, Svetomir N. Markovic, John A. Copland

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4 Scopus citations

Abstract

Patient-derived tumor xenograft (PDTX) mouse models were used to discover new therapies for naïve and drug resistant BRAFV600E-mutant melanoma. Tumor histology, oncogenic protein expression, and antitumor activity were comparable between patient and PDTX-matched models thereby validating PDTXs as predictive preclinical models of therapeutic response in patients. PDTX models responsive and non-responsive to BRAF/MEK standard of care (SOC) therapy were used to identify efficacious combination therapies. One such combination includes a CDK4/6 inhibitor that blocks cell cycle progression. The rationale for this is that the retinoblastoma protein (pRb) is 95% wildtype in BRAF mutant melanoma. We discovered that 77/77 stage IV metastatic melanoma tissues were positive for inactive phosphorylated pRb (pRb-Ser780). Rb is hyperphosphorylated and inactivated by CDK4/6:cyclin D1 and when restored to its hypophosphorylated active form blocks cell cycle progression. The addition of a CDK4/6 inhibitor to SOC therapy was superior to SOC. Importantly, triple therapy in an upfront treatment and salvage therapy setting provided sustained durable response. We also showed that CDK4/6 blockade resensitized drug resistant melanoma to SOC therapy. Durable response was associated with sustained suppression of pRb-Ser780. Thus, reactivation of pRb may prove to be a clinical biomarker of response and the mechanism responsible for durable response. In light of recent clinical trial data using this triple therapy against BRAFV600E-mutant melanoma, our findings demonstrating superior and prolonged durable response in PDTX models portend use of this therapeutic strategy against naïve and SOC resistant BRAF V600E-mutant metastatic melanoma coupled with pRB-Ser780 as a biomarker of response.

Original languageEnglish (US)
Pages (from-to)10905-10919
Number of pages15
JournalOncotarget
Volume9
Issue number13
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Cyclin dependent kinase 4/6 (CDK4/6) inhibitors
  • Melanoma
  • Mutant BRAF
  • Patient-derived tumor xenograft (PDTX)
  • Retinoblastoma (Rb)

ASJC Scopus subject areas

  • Oncology

Cite this

Harris, A. L., Lee, S. E., Dawson, L. K., Marlow, L. A., Edenfield, B. H., Durham, W. F., Flotte, T. J., Thompson, M., Small, D. L., Synnott, A. J., Markovic, S. N., & Copland, J. A. (2018). Targeting the cyclin dependent kinase and retinoblastoma axis overcomes standard of care resistance in BRAFV600E-mutant melanoma. Oncotarget, 9(13), 10905-10919. https://doi.org/10.18632/oncotarget.23649