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.
Highlights
Metastatic melanoma is a disease with poor prognosis [1], primarily due to its complex tumor heterogeneity, distinct profiles of somatic mutations involved in tumorigenesis [2], and intrinsic resistance to both chemotherapy and radiotherapy [3]
The aberrant activation of ERK and inactivation of pRb contribute to constitutive oncogenic signaling within tumor cells, which has been previously reported in BRAFV600E-mutant melanoma [25, 26].To confirm the aberrant expression of these two pathways, we examined clinical samples using a tissue microarrays (TMAs) of human stage IV melanoma tissues for pERK and pRB-Ser780
Mice were treated until study completion with indicated dosing and schedules. a, po, oral gavage; qd, everyday this, we investigated the antitumor activity of palbociclib in combination with dual dabrafenib and trametinib treatment (DT) as an upfront triple therapy combination and palbociclib as a salvage therapeutic strategy added to dual standard of care (SOC) treatment when tumors escape dual BRAF/ MEK inhibition
Summary
Metastatic melanoma is a disease with poor prognosis [1], primarily due to its complex tumor heterogeneity, distinct profiles of somatic mutations involved in tumorigenesis [2], and intrinsic resistance to both chemotherapy and radiotherapy [3]. Single agent BRAF inhibition has increased overall survival (OS) by 20% [6] and immune therapies, such as ipilimumab, have increased OS by 32%, with response rates varying between 32-45% [7, 8] Despite these improvements, varying mechanisms of resistance occur in patients. Immune therapies are associated with innate resistance, whereas targeted therapies are associated with acquired resistance [9], which the latter is often associated with reactivation of the MAPK pathway which promotes cell proliferation, drug resistance and protection from apoptosis [10] This underscores the need to identify new therapies that improve disease management and patient survival that suppress cell cycle progression, prevent or reverse drug resistance and promote cell death
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