Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer.
Ran LiThomas S C NgStephanie J WangMark PrytyskachChristopher Blake RodellHannes MikulaRainer H KohlerMichelle A GarlinDouglas A LauffenburgerSareh ParangiDaniela M DinulescuNabeel BardeesyRalph WeisslederMiles A MillerPublished in: Nature nanotechnology (2021)
Nanoparticulate albumin bound paclitaxel (nab-paclitaxel, nab-PTX) is among the most widely prescribed nanomedicines in clinical use, yet it remains unclear how nanoformulation affects nab-PTX behaviour in the tumour microenvironment. Here, we quantified the biodistribution of the albumin carrier and its chemotherapeutic payload in optically cleared tumours of genetically engineered mouse models, and compared the behaviour of nab-PTX with other clinically relevant nanoparticles. We found that nab-PTX uptake is profoundly and distinctly affected by cancer-cell autonomous RAS signalling, and RAS/RAF/MEK/ERK inhibition blocked its selective delivery and efficacy. In contrast, a targeted screen revealed that IGF1R kinase inhibitors enhance uptake and efficacy of nab-PTX by mimicking glucose deprivation and promoting macropinocytosis via AMPK, a nutrient sensor in cells. This study thus shows how nanoparticulate albumin bound drug efficacy can be therapeutically improved by reprogramming nutrient signalling and enhancing macropinocytosis in cancer cells.
Keyphrases
- advanced non small cell lung cancer
- pi k akt
- magnetic resonance
- cell proliferation
- stem cells
- emergency department
- mouse model
- induced apoptosis
- high throughput
- epidermal growth factor receptor
- signaling pathway
- skeletal muscle
- cell cycle arrest
- squamous cell carcinoma
- blood pressure
- adipose tissue
- drug delivery
- blood glucose
- adverse drug
- protein kinase
- growth hormone