Inhibition of respiratory complex I (CI) is an emerging anticancer strategy, whose specificity and efficacy of numerous inhibitors remain however elusive. Cancer cell models lacking CI reveal the specificity of EVP 4593 and BAY 872243 in inducing antiproliferative effects not associated with apoptosis, selectively via CI, reducing possible side effects. Preliminary in vivo studies show a slowing of tumor growth in animals treated with EVP 4593, which emerges as the most potent inhibitor.
Because of its role in metabolic reprogramming, and its high mutation frequency in human malignancies, potential mechanisms of adaptation to anti-CI therapy based on TP53 mutational status have been investigated. Auxotrophy by aspartate, a metabolic hallmark of tumor cells with CI damage, causes a blockade of mTORC1-dependent protein synthesis in cell lines with mutated or null p53, inducing metabolic collapse. Conversely, activation of the energy sensor AMPK promotes partial recovery of aspartate synthesis in cell lines with the wild-type P53, which is able to sustain enhanced anaplerosis through SCO2, an assembly factor of respiratory complex IV.
In order to translate these results into a preclinical model, cultures of explanted human tumors were optimized using the U-CUP bioreactor. The model chosen was high-grade serous ovarian cancer (HGSOC), from frozen tissue, because of the high frequency of driver mutations in TP53. Frozen tissues preserve the heterogeneity of cellular components of the tissue of origin and they are characterized by actively proliferating cells without activation of apoptosis. Preliminary data show a trend of tumor area reduction in EVP 4593-treated tissues and support the use of the preclinical model in the study of novel CI inhibitors by exploiting primary tissue from cancer patients.