When the researchers tested a PAK inhibitor, PF-3758309, they found that cells resistant to both BRAF inhibition and combination inhibition were sensitive to the drug, and that PAK inhibition slowed cell-cycle progression.
They also found that ectopic expression of active mutant PAK1 resulted in drug resistance to MAPK inhibitors in a parental cell line.
“This group has made a pretty convincing argument that PAK signaling is involved in the majority of BRAF/MEK resistant melanomas,” Dr Funchain said.
Future research into PAK signaling in humans would, however, require use of a different PAK inhibitor. PF-3758309 was used in a prior phase 1 study, but did not appear to come through in high enough levels in the human body and had some adverse effects, she added.
Dr Funchain also noted that even if a PAK inhibitor were successfully developed and tested, use of a PAK inhibitor would not be “one size fits all.”
“In all of their experiments, [the researchers] always had one cell line that did not behave like the others, and that is partially science and partially biology,” Dr Funchain noted. “They have made a convincing argument that a good number of BRAF and MEK inhibitor resistant tumors would probably be sensitive, if not to a PAK inhibitor, then to something in that pathway.”
- Lu H, Liu S, Zhang G, et al. PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature. 2017;550(7674):133-6. doi: 10.1038/nature24040