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New Research Published by Oncotarget Finds Method to Combat Drug Resistance in Thyroid Cancer

The past few years has seen enormous steps taken in cancer treatment. A joint study conducted by Harvard Medical School and University of Parma in Parma, Italy found an alternative means of treating Papillary thyroid carcinoma (PTC), one of the most common forms of thyroid cancer. The study found that combining two separate cancer medications (palbociclib and vemurafenib) had a synergistic effect that resulted in more cell death than the dosage of a single medicine. The study was featured in Oncotarget with the title, “Vemurafenib-resistance via de novo RBM genes mutations and chromosome 5 aberrations is overcome by combined therapy with palbociclib in thyroid carcinoma with BRAFV600E.”

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Common Papillary Thyroid Carcinoma Treatments – Vemurafenib

The most commonly administered medication for PTC is vemurafenib, but the treatment often has diminishing returns as patients gradually build up resistance to the drug. The root cause for PTC is a mutation in cells, specifically in the BRAF gene, and the mutation has been labelled RAFV600E. When researchers looked to find the root cause of why vemurafenib began to fail, they found that RAFV600E cells subject that have been subject to the drug over time were missing the P16 in cancer cells.

Vemurafenib Leads to Loss of P16 Genes

The P16 gene regulates the creation of protein essential the cell reproduction. The loss of P16 could be linked to why PTC cancer cells continue to reproduce after being treated by vemurafenib – the inability to regulate or prevent the creation of proteins means that the cells are always pushing to replicate, even though certain criteria may not be fulfilled.

Loss of P16 Genes can be Alleviated by Targeting CDK4/6 Proteins – Palbociclib

Members of the research team recognized that vemurafenib will eventually lead to the loss of P16 genes in cancer cells, so they needed to find a way to get PTC cells to stop regulating. One specific way that P16 regulates cell replication is through controlling the formation of a protein complex called CDK4/6, which is required for DNA to be copied during cell replication. The team found that it was possible to directly target CDK4/6 production, which essentially mimics the role of the missing P16 gene. To combat CDK4/6 production, the team identified an existing drug approved by the FDA for late stage breast cancer treatment: palbociclib.

The Synergistic Results of Administering both Vemurafenib and Palbociclib

The team tested a combination of both vemurafenib and palbociclib on vemurafenib-resistant, RAFV600E–positive PTC patients, they found that the two-pronged attack caused more cell death than either solution would alone. By targeting both the initial RAFV600E mutation and the CDK4/6 production, it enabled the treatment to cast a wider net over existing PTC ells. Even though vemurafenib led to long-term degradation of P16 genes, that problem was mitigated by the effects of palbociclib. This research proves that the combined therapy works on PTC cells with either primary or secondary resistance.

A key takeaway from this test is that it enables a potential new strategy to treat vemurafenib-resistant patients with PTC, as the introduction of palbociclib essentially solves the main side effect of vemurafenib.

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