In Cancer Discovery, researchers in the US and Australia report that pre-existing MEK1 exon 3 mutations in V600E/KBRAF melanomas don't confer resistance to BRAF inhibitors. The team sequenced MEK1/2 exon 3 in 31 melanomas at disease diagnosis and at progression, and found that five of them carried concurrent somatic BRAF/MEK1 activating mutations. Three of those five patients showed objective responses to BRAF inhibitors, consistent with the overall response rate to these drugs. "MEK1-mutant expression in V600E/KBRAF melanoma cell lines resulted in no significant alterations in p-ERK1/2 levels or growth-inhibitory sensitivities to BRAFi, MEK1/2 inhibitor, or their combination," the authors write. "Thus, activating MEK1 exon 3 mutations identified herein and concurrent with V600E/KBRAF do not cause BRAF [inhibitor] resistance in melanoma."
Also in Cancer Discovery, researchers at Harvard Medical School and Dana-Farber Cancer Institute present their functional characterization of an isoform-selective inhibitor of PI3K-p110β. The team used a panel of PI3K isoform-specific cellular assays to screen compounds that act against kinases in the PI3K superfamily. They identified a selective p110β inhibitor called KIN-193, which they say is "efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss." When the drug was profiled across a panel of 422 human tumor cell lines, the team found that the cancer cells' PTEN mutation status strongly correlated with their response to KIN-193. "Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms," they add.