Abstract 2683: Activation of MAP kinase pathway in breast cancer cell lines by polyisoprenylated cysteinyl amide inhibitors (PCAIs) causes cell death

Abstract Female breast cancer has now surpassed lung cancer as the most common cancer overall in both sexes with an estimated 2.3 million new cases, representing 11.7% of all cancer cases worldwide in 2020. Triple negative breast cancer (TNBC) has been the subject of intensive studies due to its aggressive nature which makes it difficult to treat. Since inclusive treatment for this type had been elusive for decades, it is thus imperative to develop new therapeutic agents to mitigate its deadly effects. PCAIs are novel compounds designed to mimic the essential posttranslational modifications of G-proteins such as KRAS. This study elucidates the effect of the PCAIs downstream of KRAS, specifically on the mitogen activated pathway kinase (MAPK) enzymes. Two breast cancer cell lines, MDA-MB-468 and MDA-MB-231, were used to determine the levels of phosphorylation in several MAPK pathway enzymes. After exposure of the cells to varying concentrations of PCAIs (NSL-YHJ-2-27) for 48 hours, western blot results showed remarkable differences in the phosphorylated levels of the respective enzymes in cells treated with 5 µm of the PCAIs as compared to the control (NSL-YHJ-2-62). Interestingly, the cell lines reacted differently after treatment, in which MDA-MB-468 cells showed increased levels of phosphorylated MEK, ERK, and 90RSK by 122, 273 and 242%, respectively. However, in MDA-MB-231, only the phosphorylated 90RSK showed an increase of 105% and no changes in the other two enzymes. Moreover, a very distinct difference was observed in the levels of phosphorylated BRAF (p-BRAF) and CRAF (p-CRAF). In MDA-MB-231 cells, no change in p-BRAF levels while a 184% increase in p-CRAF were observed. In MDA-MB-468, p-BRAF increased by 41% and p-CRAF decreased by 58%. The differences in the response of the cell lines may reflect their unique genetics. These results show the ability of the PCAIs to interfere with the MAPK pathway. As this signaling cascade plays a very important role in cell response as well as in the progression of cancers, therefore, therapeutics targeting this pathway have a great potential in the development of treatments not only for TNBC but also for other kinds of cancers. Citation Format: Jassy Mary Lazarte, Nada Tawfeeq, Yonghao Jin, Nazarius Lamango. Activation of MAP kinase pathway in breast cancer cell lines by polyisoprenylated cysteinyl amide inhibitors (PCAIs) causes cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2683.