As the “fun in the sun” season is currently in full swing for the northern hemisphere, it would seem an appropriate time to discuss the effects of UV damage to skin cells, especially since the number of drug-resistant melanoma cases are on the rise. Moreover, greater than half of all melanoma patients have mutations in the seronine/threonine protein kinase BRAF and become resistant to BRAF inhibitor treatments—often the first-line therapy used to treat many melanoma cases.
However, a collaboration of scientists led by a team at the Moffit Cancer Center believe they may be able to circumvent cancer progression, as they have uncovered a novel mechanism that leads melanoma cells to develop resistance to drugs that target BRAF.
“This study gives important new insights into why nearly all melanoma patients fail targeted therapy,” said Keiran Smalley, Ph.D., associate member of the Tumor Biology Program at Moffitt and senior author on the current study.
The findings from this study were published recently in Oncogene through an article entitled “Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells.”
In addition to the high incidence of BRAF mutations, another gene that is frequently mutated in melanoma is PTEN. Furthermore, studies have shown that melanoma patients with both BRAF and PTEN mutations may have a poorer response to the BRAF inhibitor molecules dabrafenib and vemurafenib.
The investigators wanted to determine the mechanism responsible for resistance to BRAF inhibitors and utilized advanced proteomic techniques to evaluate the signaling profile of melanoma cells treated with BRAF inhibitors.
“In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null,” explained the scientists. “Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent.”
Most interestingly, the researchers found that BRAF inhibitors caused BRAF and PTEN mutant melanoma cells to increase levels of fibronectin. Fibronectin is an extracellular matrix protein that is secreted to the space surrounding most cells. The scientists found that higher levels of fibronectin allowed melanoma cells to form their own protective environment that reduced the ability of BRAF inhibitors to kill tumor cells.
Importantly, the Moffit researchers found that targeting tumors with BRAF inhibitors combined with a drug that targets the protective environment, a PI3K inhibitor compound, significantly boosted the killing efficiency of the BRAF inhibitor.
“Targeting the protective environment is one way of delivering more durable therapeutic responses to our patients,” stated lead author Inna Fedorenko, Ph.D., post-doctoral fellow at Moffitt.