Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy-Induced Necrosis.

Unlabelled: Several emerging therapies kill cancer cells primarily by inducing necrosis. As necrosis activates immune cells, potentially, uncovering the molecular drivers of anticancer therapy-induced necrosis could reveal approaches for enhancing immunotherapy efficacy. To identify necrosis-associated genes, we performed a genome-wide CRISPR-Cas9 screen with negative selection against necrosis-inducing preclinical agents BHPI and conducted follow-on experiments with ErSO.

Computational approaches to identify a novel binding site of BHPI on estrogen receptor alpha.

3,3-bis(4-hydroxyphenyl)-7-methyl-1,3,dihydro-2H-indol-2-one (BHPI) is a biomodulator of Estrogen Receptor alpha (ERα) that targets ERα positive cancer cells by activating the unfolded protein response (UPR). BHPI induces strong and sustained activation of this pathway, eventually resulting in necrotic cell death. While much is known about how BHPI triggers the UPR leading to necrotic cell death, it is not known how BHPI binds to its putative molecular target, ERα.

Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6.

1. Metoclopramide is a widely used clinical drug in a variety of medical settings with rare acute dystonic events reported. The aim of this study was to assess a previous report of inactivation of CYP2D6 by metoclopramide, to determine the contribution of various CYPs to metoclopramide metabolism, and to identify the mono-oxygenated products of metoclopramide metabolism.