Cancer

Cell culture and mouse studies suggest inhibiting GPX4 could help treat relapsing, drug-resistant cancers. In human breast, lung, melanoma and ovarian cancer cell lines, a GPX4 inhibitor tool compound induced higher levels of ferroptosis in persister cells -- a subset of tumor cells that survives targeted therapy -- than in parental cells. In a xenograft mouse model of melanoma that responds to treatment then relapses, administration of Mekinist trametinib and Tafinlar dabrafenib to shrink tumors followed by GPX4 knockout delayed relapse for at least two weeks compared with normal GPX4 expression. Next steps could include testing GPX4 inhibition in other models of relapsing and/or drug-resistant cancers.

Japan Tobacco Inc. and Novartis AG market Mekinist, an inhibitor of MAP kinase kinase 1 (MAP2K1; MEK1) and MAP2K2, to treat melanoma, have the drug approved to treat non-small cell lung cancer (NSCLC) and have the compound in Phase I/II through Phase II testing for other solid tumors...