Tucatinib inhibited the phosphorylation of HER2 in a L755S mutant MCF-10A cell line and inhibited the growth of 3 L755S mutant tumor models derived from colorectal, gastric and non-small cell lung cancer...Importantly, tucatinib is active in models containing the L755S HER2 mutation which has been associated with lapatinib resistance preclinically (1), and trastuzumab resistance clinically (2)...Taken together, these results support the idea that HER2 selective inhibition by tucatinib can block oncogenic signaling elicited by mutant HER2, and that it could potentially provide clinical benefit in patients with cancers with activating HER2 mutations.