22 THE SCIENTIST | the-scientist.com
I
n the early 2000s, back when biolo-
gist Olivia Rossanese worked as an
investigator at GlaxoSmithKline,
fighting cancer was an exercise in brute
force. Researchers at the company had
set their sights on developing inhibi-
tors of B-Raf, a protein kinase involved
in cell signaling that becomes dysfunc-
tional in many cancers, and “what we
were thinking was that we needed to hit
this... protein so hard,” says Rossanese.
“ Yo u had to inhibit it 99.999 percent to
shut down the signaling pathway.”
In 2008, Rossanese and her GSK col-
leagues discovered just the sort of com-
pound they were after: a small mole-cule, dabrafenib, that potently inhibited
B-Raf and showed striking effects in mel-
anoma patients with certain mutations
in the BRAF gene. With dabrafenib, says
Rossanese, “we see really amazing
responses, and melanomas go a w a y.” The
drug was approved by the US Food and
Drug Administration (FDA) in 2013.
But in a majority of patients, the
effect doesn’t last long. The cancer usu-
ally comes back within just six months
or so—and when it does, it’s resistant
to dabrafenib. GSK’s data showed that
less than half of metastatic melanoma
patients treated with dabrafenib alone
survived more than two years.New therapeutic approaches in oncology take aim at the very thing that
makes cancer so untreatable: its ability to evolve drug resistance.BY CATHERINE OFFORD