Affiliation:
1. Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland
Abstract
Background: Although BRAFV600/MEK inhibitors improved the treatment of melanoma patients, resistance is acquired almost inevitably. Methods: Trametinib withdrawal/rechallenge and MCL-1 inhibition in trametinib-resistance models displaying distinct p-ERK1/2 levels were investigated. Results: Trametinib withdrawal/rechallenge caused reversible changes in ERK1/2 activity impacting the balance between pro-survival and pro-apoptotic proteins. Reversible alterations were found in MCL-1 levels and MCL-1 inhibitors, BIM and NOXA. Taking advantage of melanoma cell dependency on MCL-1 for survival, we used S63845. While it was designed to inhibit MCL-1 activity, we showed that it also significantly reduced NOXA levels. S63845-induced apoptosis was detected as the enhancement of Annexin V-positivity, caspase-3/7 activation and histone H2AX phosphorylation. Percentages of Annexin V-positive cells were increased most efficiently in trametinib-resistant melanoma cells displaying the p-ERK1/2low/MCL-1low/BIMhigh/NOXAlow phenotype with EC50 values at concentrations as low as 0.1 μM. Higher ERK1/2 activity associated with increased MCL-1 level and reduced BIM level limited pro-apoptotic activity of S63845 further influenced by a NOXA level. Conclusions: Our study supports the notion that the efficiency of an agent designed to target a single protein can largely depend on the phenotype of cancer cells. Thus, it is important to define appropriate phenotype determinants to stratify the patients for the novel therapy.
Funder
Medical University of Lodz
Reference97 articles.
1. Melanoma Research Foundation. The state of melanoma: Emergent challenges and opportunities;Atkins;Clin. Cancer Res.,2021
2. European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment—Update 2022;Garbe;Eur. J. Cancer.,2022
3. Florent, L., Saby, C., Slimano, F., and Morjani, H. (2023). BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge. Cancers, 15.
4. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma;Robert;N. Engl. J. Med.,2019
5. Melanoma classification and management in the era of molecular medicine;Rashid;Dermatol. Clin.,2023