Credit: University of Leicester
Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.
The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.
Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).
But new results in a patient with HCL suggest otherwise.
Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.
The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.
They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.
But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.
“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”
The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.
A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.
“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.
