P21-activated kinases (PAKs) may be a pivotal mediator of resistance to BRAF inhibition and combined BRAF and MEK inhibition in patients with BRAF-mutant melanomas, according to research recently published in Nature.1

Use of mitogen-activated protein kinase (MAPK) pathway targeted therapies (BRAF/MEK inhibitors) and immune checkpoint inhibitors have changed the management and significantly improved outcomes for patients with advanced melanoma. About 25% of patients now continue treatment with combined BRAF/MEK inhibitors for years.

“About three-quarters of patients, however, have cancer that becomes resistance to these drugs,” said Pauline Funchain, MD, of the department of hematology and medical oncology at the Cleveland Clinic in Ohio. “If we can learn how the cancer is going to side-step these drugs, then we can essentially try to stop the side-step.”

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In the Nature letter, researchers investigated underlying mechanisms leading to acquired resistance to BRAF and BRAF/MEK inhibition. Consistent with prior research, resistance to BRAF inhibition was mediated by ERK pathway reactivation. Resistance to combined BRAF/MEK inhibition, however, was mediated by mechanisms independent of the ERK pathway in many of the resistant cell lines.

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Instead, PAKs became activated in cells with the drug resistance. The researchers used reverse-phase protein array and found distinct mechanisms by which PAKs mediated resistance to these therapies.

“In BRAF inhibition-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK,” the researchers wrote. “In cells that are resistant to the combined therapy, PAKs regulate JNK and β-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK.”