UPR/ATF4/Noxa pathway over-activation through SERCA2 inhibition or ONC201 treatment combined with ABT-737 triggers apoptosis in chemoresistant ovarian cancer cells and patient-derived tumour organoids

Ovarian cancer has a poor clinical prognosis due to chemoresistance following carboplatin/paclitaxel treatment. This phenomenon can be explained by an imbalanced ratio of [anti-apoptotic (BCL-xL/MCL-1)] to [pro-apoptotic (Noxa, BIM, PUMA)] BCL-2 family members that prevents apoptosis initiation. Consequently, any treatment capable of counterbalancing this ratio could be beneficial in the management of ovarian cancer. Calcium signalling is strongly implicated in resistance to apoptosis, as it depends on, but also regulates, the expression of the ratio of BCL-2 family members, making calcium-targeted strategies relevant to overcoming chemoresistance. Knowing that SERCA2 calcium pumps regulation play a major role in controlling the ER stress-induced UPR response that could lead to pro-apoptotic protein up-regulation and cell death, we therefore evaluated whether their inhibition could elicit apoptosis or sensitise ovarian cancer cells to other therapeutic strategies. For this purpose, the platinum-resistant cell line, OAW42-R, was treated with anti-SERCA2 strategies which revert the BCL-2 family member expression ratio in favour of pro-apoptotic proteins. Combination with the BH3-mimetic ABT-737 exacerbates this imbalance not only by inhibiting BCL-xL activity but also through over-induction of the UPR/ATF4/Noxa axis leading to MCL-1 inhibition. This dual effect of ABT-737 upon ER stress fully suppresses the anti-apoptotic capacities of cancer cells leading to massive mitochondrial apoptosis. This point was supported with ONC201, the first member of the imipridone family of anticancer drugs to enter the clinic, whose ability to trigger UPR/ATF4/Noxa led to apoptosis commitment when it was combined with ABT-737 treatment. The therapeutic efficacy of these combinations was also proved in patient-derived-tumour-organoids models (PDTO) leading to their structural disintegration and reduced viability. Collectively, our study highlights that ABT 737, through BCL-xL inhibition and synergy with ER stress inducers, triggers ovarian cancer death, offering promising strategies for overcoming chemoresistance in relapsed ovarian cancer.