Targeted chemotherapy overcomes drug resistance in melanoma.
Jingyin YueRoberto VendraminFan LiuOmar LopezMonica G ValenciaHelena Gomes Dos SantosGabriel GaidoshFelipe BeckedorffEzra BlumenthalLucia SperoniStephen D NimerJean-Christophe MarineRamin ShiekhattarPublished in: Genes & development (2020)
The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed "targeted chemotherapy" by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma. Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy. Phendione treatment reduces tumor growth of BRAFV600E-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRASQ61R-driven melanoma, a cancer with no effective therapy. Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAFV600E PDX highlighting its effectiveness in combating the advent of drug resistance.
Keyphrases
- drug resistant
- multidrug resistant
- acinetobacter baumannii
- dna damage
- small molecule
- dna damage response
- skin cancer
- locally advanced
- cancer therapy
- randomized controlled trial
- oxidative stress
- systematic review
- dna repair
- induced apoptosis
- drug delivery
- rectal cancer
- chemotherapy induced
- papillary thyroid
- signaling pathway
- radiation therapy
- squamous cell carcinoma
- pseudomonas aeruginosa
- cell free
- cell cycle
- binding protein
- cell death
- bone marrow
- endoplasmic reticulum stress
- amino acid
- squamous cell