Aramchol as a therapeutic for inflammatory breast cancer in Vitro

Aramchol, an inhibitor of Stearoyl-CoA desaturase, synergizes with the multi-kinase inhibitor regorafenib to kill GI tumor cells in vitro and in vivo. A phase I trial in GI tumor patients combining these drugs will open in 2027. Aramchol preferentially concentrates in tissues with high lipid content. Inflammatory breast cancer has a dismal prognosis and new approaches to treat this form of the disease are needed. A standard of care breast cancer therapeutic, the cyclin-dependent kinase 4/6 inhibitor palbociclib, interacted with aramchol as a single agent and with [aramchol plus regorafenib] in vitro to kill a genetically diverse cohort of breast cancer cells, including inflammatory breast cancer. Aramchol interacted with doxorubicin and docetaxel to kill breast cancer cells. Treatment of breast cancer cells with [aramchol plus regorafenib] caused dephosphorylation of mammalian target of rapamycin, mTORC1 S2448, and increased phosphorylation of autophagy gatekeeper/regulator ATG13 S318, effects that were magnified by inclusion of palbociclib. Primary drug-response signaling from ataxia telangiectasia mutated through the AMP-dependent protein kinase was required to cause both dephosphorylation of mTORC1 and ATG13 activation. Palbociclib interacted with [aramchol plus regorafenib] to cause additional autophagosome formation and autophagic flux. Knock down of: Beclin1/ATG5/LAMP2 (macroautophagy); CD95/FADD (death receptor); or eIF2a (endoplasmic reticulum stress) significantly reduced autophagosome/autolysosome formation, and this was mirrored in data sets obtained when defining drug-induced mechanisms of cell death. Our in vitro data conclude that aramchol, alone or combined with regorafenib, has potential to become a new approach to enhance the efficacy of standard of care breast cancer therapeutics.