| Autor: |
Foda BM; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48823, USA.; Molecular Genetics and Enzymology Department, National Research Centre, Dokki 12622, Egypt., Neubig RR; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48823, USA.; Nicholas V. Perricone, M.D. Division of Dermatology, Department of Medicine, Michigan State University, East Lansing, MI 48823, USA. |
| Jazyk: |
angličtina |
| Zdroj: |
International journal of molecular sciences [Int J Mol Sci] 2023 Sep 07; Vol. 24 (18). Date of Electronic Publication: 2023 Sep 07. |
| DOI: |
10.3390/ijms241813785 |
| Abstrakt: |
Cutaneous melanoma is the deadliest skin cancer. Most have Ras-MAPK pathway (BRAF V600E or NRAS) mutations and highly effective targeted therapies exist; however, they and immune therapies are limited by resistance, in part driven by small GTPase (Rho and Rac) activation. To facilitate preclinical studies of combination therapies to provide durable responses, we describe the first mouse melanoma lines resistant to BRAF inhibitors. Treatment of mouse lines, YUMM1.7 and YUMMER, with vemurafenib (Vem), the BRAF V600E -selective inhibitor, resulted in high-level resistance (IC 50 shifts 20-30-fold). Resistant cells showed enhanced activation of Rho and the downstream transcriptional coactivator, myocardin-related transcription factor (MRTF). Resistant cells exhibited increased stress fibers, nuclear translocation of MRTF-A, and an increased MRTF-A gene signature. Pharmacological inhibition of the Rho/MRTF pathway using CCG-257081 reduced viability of resistant lines and enhanced sensitivity to Vem. Remarkably, co-treatment of parental lines with Vem and CCG-257081 eliminated resistant colony development. Resistant cells grew more slowly in vitro, but they developed highly aggressive tumors with a shortened survival of tumor-bearing mice. Increased expression of immune checkpoint inhibitor proteins (ICIs) in resistant lines may contribute to aggressive in vivo behavior. Here, we introduce the first drug-resistant mouse melanoma models for assessing combinations of targeted and immune therapies. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
|
Nepřihlášeným uživatelům se plný text nezobrazuje |
K zobrazení výsledku je třeba se přihlásit.
|
