The BCL-2 inhibitor ABT-199/venetoclax synergizes with proteasome inhibition via transactivation of the MCL-1 antagonist NOXA.

Enhanced expression of anti-apoptotic B-cell lymphoma 2 (BCL-2) protein is frequent in cancer. Targeting of BCL-2 with the specific inhibitor ABT-199 (Venetoclax) has significant clinical activity in malignant diseases such as chronic lymphocytic leukemia and multiple myeloma. The small molecule drug ABT-199 mimics the pro-apoptotic BCL-2 homology domain 3 of BH3-only proteins and blocks the hydrophobic BC-groove in BCL-2. We have previously shown that ABT-199 synergizes with the proteasome inhibitor (PI) bortezomib in soft tissue sarcoma derived cells and cell lines to induce apoptosis. Synergistic apoptosis induction relies on the pore-forming effector BAX and expression of the pro-apoptotic BH3-only protein NOXA. Bortezomib augments expression of NOXA by blocking its proteasomal degradation. Interestingly, shown here for the first time, expression of NOXA is strongly enhanced by ABT-199 induced integrated stress response (ISR). ISR transcription factors ATF3 & ATF4 mediate transactivation of the BH3-only protein NOXA which specifically inhibits the anti-apoptotic MCL-1. Thus, NOXA potentiates the efficacy of the BCL-2 inhibitor ABT-199 by simultaneous inhibition of MCL-1. Hence, ABT-199 has a double impact by directly blocking anti-apoptotic BCL-2 and inhibiting MCL-1 via transactivated NOXA. By preventing degradation of NOXA PIs synergize with ABT-199. Synergism of ABT-199 and PIs therefore occurs on several, previously unexpected levels. This finding should prompt clinical evaluation of combinatorial regimens in further malignancies.

Determination of Both TP53 Mutation Status and the Amount of p53 Protein has Limited Diagnostic Importance for Patients with Ovarian Cancer.

BACKGROUND: Ovarian cancer is one of the most aggressive types of gynecologic cancers. Many patients have a relapse within two years after diagnosis and subsequent therapy. Among different genetic changes generally believed to be important for the development of cancer, TP53 is the most common mutation in the case of ovarian tumors. OBJECTIVE: Our work aims to analyze the outcomes of different comparisons based on the overall survival of ovarian cancer patients, the determination of TP53 status and the amount of p53 protein in tumor tissues. METHODS: We analyzed and compared a collective of 436 ovarian patients' data. The extracted data include TP53 mutation status, p53 protein level and information on the overall survival. Values for p53 protein level in dependence of the TP53 mutation status were compared using the Independent Samples t-Test. Survival analyses were displayed by Kaplan- Meier plots, using the log-rank test to check for statistical significance. RESULTS: We have not found any statistically significant correlations between the determination of TP53 status or the amount of p53 protein in tumor tissues and the overall survival of ovarian cancer patients. CONCLUSION: In ovarian tumors the determination of both the TP53 status as well as the p53 protein amount has only limited diagnostic importance.