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

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.

Current Advances in the Treatment of BRAF-Mutant Melanoma

“…These have emerged as alternative treatment options for treating metastatic melanoma patients. Preclinical and clinical trials evaluating the efficacy of various PI3K and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are also initiated [17][18][19][20][21][22].…”

Precision Medicine Tools to Guide Therapy and Monitor Response to Treatment in a HER-2+ Gastric Cancer Patient: Case Report

“…Interestingly, the PDX model established from the primary gastric tumor could predict patient response of the lung metastatic lesions, and this, months later, and despite the tumor evolution that could have taken place after capecitabine treatment. Although many reports have correlated clinical drug response with response in PDXs, the majority of these studies have done so in a retrospective manner (8, 18–21). The use of PDXs to guide clinical treatment decisions in a prospective manner or in real-time is challenging and very few cases have been published (22–24).…”

Targeted Therapy in Melanoma and Mechanisms of Resistance

“…In fact, cyclin D1 regulates proliferation while binding to CDK4 and CDK6, which in turn activates retinoblastoma protein (pRb) and promotes cell cycle progression [ 84 ]. CCND1 amplification has been observed in 20–38% of melanoma samples, which indicates that a large group of patients is potentially resistant to BRAFi and could benefit from treatment with a CDK4/6 inhibitor [ 84 , 85 , 86 ]. In cells in which the CCND1 gene has been amplified, there is an increase in cyclin D1 production, and as a consequence, BRAF inhibition is not sufficient to inhibit proliferation [ 83 ].…”