Karen Toy
Genentech, Molecular Biology, Department Member
The RAS/RAF/MEK pathway is activated in over 30% of human cancers, most commonly via mutation in the K-ras oncogene but also via mutations in BRAF. Several allosteric MEK inhibitors, aimed at treating tumors with RAS/RAF pathway... more
The RAS/RAF/MEK pathway is activated in over 30% of human cancers, most commonly via mutation in the K-ras oncogene but also via mutations in BRAF. Several allosteric MEK inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK resistant cell lines retained their addiction to the MAPK pathway, as evide...
