Targeting Increased Polyamine Transport of Resistant Melanomas
Abstract
Although BRAF inhibitors (BRAFi) significantly improve survival of patients with metastatic melanoma, recurrences occur within several months. Development of BRAFi-resistance enriches for metastatic cancer stem cells (CSC) and increases tumor-promoting macrophages, both of which require polyamines. The objective of this study was to exploit the oncogene-induced polyamine transport system (PTS) activity in melanoma cells by targeting the PTS with a novel arylmethyl-polyamine (AP) compound that is cytotoxic upon cell entry. We hypothesized that AP 1) would kill BRAFi-resistant melanoma CSCs as a result of induced PTS activity and 2) would block CXCR4 signaling in metastatic tumor cells and stromal macrophages, thus inhibiting melanoma progression and metastasis. We proposed the following specific aims:1) to compare effects of AP on mutant and wildtype BRAF melanoma cells and on melanoma tumor cell survival in macrophage co-culture assays with BRAFi2) to evaluate whether AP increases the anti-tumor effect of BRAFi in mice We found that BRAF mutant melanoma cells have higher PTS activity and are more sensitive to AP compared to BRAF wild type cells. Although cancer stem cell-like subpopulations of BRAF mutant melanoma cells were resistant to BRAFi, they were more susceptible to cytotoxic activity of AP compared to proliferating populations of the same cells. Moreover, AP inhibited M2 polarization and VEGF production by macrophages that provides a survival advantage for melanoma tumor cells treated with BRAFi. Co-treatment with the BRAF inhibitor, PLX4720, and AP decreased tumor-promoting macrophages and significantly delayed the recurrence of PLX4720-resistant melanoma tumors that occurred in animals treated with PLX4720 alone. Our work has greatly added to our understanding of the PTS in tumors and offers a novel therapy (AP) that can harness this transport system to better treat resistant forms of metastatic melanoma.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2019
- Accession Number
- AD1086319
Entities
People
- Susan Gilmour
Organizations
- Lankenau Institute for Medical Research