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Sep 20, 2013

Cutting Melanoma Off at the Pass

  • Scientists at the Wistar Institute describe in an online article in Cell Reports the mechanism by which melanoma can evolve resistance to a combination of BRAF and MEK inhibitors. They found that resistant melanomas acquired a mutation in the MEK2 gene and multiple copies of the mutant BRAF oncogene, simultaneously decreasing the sensitivity to both drug targets.

    “We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib,” wrote the researchers in the journal article (“Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma”). “We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib.”

    Their findings also uncovered a new potential target for melanoma therapy, a protein called S6K. Additionally, early studies in a laboratory model for melanoma show that a triple combination of drug inhibitors halted the growth of resistant tumors.

    “Combining BRAF and MEK inhibitors was conceived as a one-two punch against the MAP kinase pathway,” said Jessie Villanueva, Ph.D., assistant professor in Wistar’s NCI-designated cancer center and member of the Wistar Institute Melanoma Research Center. “While it is considered successful in the clinic, some tumors do not respond and others develop resistance, underscoring the need for new therapeutic strategies.”

    As cancer clinicians began to see patients develop resistance to BRAF and MEK inhibitors, the Wistar team began to explore the mechanisms by which tumors develop resistance. They found that melanoma cells used different tactics for each enzyme. Mutations in MEK2, for example, would render anti-MEK therapies ineffective. To defeat BRAF inhibitors, surviving melanoma cells exhibited numerous copies of the mutant BRAF gene, enough to overpower anti-BRAF drugs.

    “There were simply too many copies of BRAF to block, it became a numbers game, and the mutation was winning,” said Dr. Villanueva. “Increasing the dosage of BRAF inhibitors could be one solution, but that cannot be done in patients without causing serious toxic effects.”

    A possible answer, they reasoned, was in the PI3K/mTOR pathway, a network of signaling enzymes often active within melanoma cells. However, they could find no sign that any of the “usual suspects”—points along the pathway commonly known to be involved in cancers—had any evident part in BRAF/MEK resistance. It was not until they examined farther “downstream” that they found persistent activation of S6K, an enzyme that appears to be at the point where P13K/mTOR and MAP kinase pathways merge.

    So the researchers tried combinations of inhibitors against BRAF, MEK, and PI3K/mTOR (as there are currently no effective S6K inhibitors) in a mouse model of melanoma. “With a triple combination of drugs, the tumors slow down and just stop growing,” Dr. Villanueva explained.

    Although a cocktail of two drugs (a combination of BRAF and PI3K/mTOR inhibitors, for example) might work, they postulated that using three drugs could be more potent and counterintuitively less toxic at the same time. “We followed these mice with melanoma for three weeks, tumors remain stable, and mice did not show any evident signs of toxicity,” noted Dr. Villanueva.

    According to the Wistar scientist, “we now we have a mechanism and a rational approach to develop both new drugs and more effective combinations aimed at solving drug resistance in melanoma. Our findings might also offer important lessons for other forms of metastatic cancer.”



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