Not sure if this has been posted before, but one first-line...

Not sure if this has been posted before, but one first-line treatment for Pancreatic cancer, Gemcitabine, has a study discussing FTO as being responsible for Gemcitabine treatment resistance in Pancreatic cancer. The study of 50 individuals revealed that patients with highly expressed FTO have a poor prognosis. Likewise, tissues resistant to Gemcitabine showed a high level of FTO. FTO knockdown increased treatment sensitivity.

Interestingly, knockdown of FTO lowered the protein levels of a downstream target called NEDD4 which in turn significantly lowered the levels of an enzyme called RRM1. RRM1 has been shown to be clinically significant in Lung, Breast and Pancreatic cancer - ie levels negatively associated with patient survival.

Gemcitabine is now a generic but once had sales of US $1.7b a year (2008) and was originally approved when it was shown to be superior to 5-FU in PC.

https://www.researchsquare.com/article/rs-1902113/v1

Results: FTO was substantially expressed in cells and tissues that were resistant to gemcitabine. Functionally, FTO enhanced gemcitabine resistance of pancreatic cancer in vitro. Depletion of FTO inhibited tumor growth of gemcitabine resistance cells in vivo. By immunoprecipitation/massSpectrometry we found FTO protein can be bound to USP7 and deubiquitinated by USP7 and lead to the upregulation of FTO. Mechanistically, FTO knockdown substantially reduced the expression level of NEDD4 in an m6A dependent manner. FTO enhanced the mRNA stability of NEDD4 through targeting its exonic regions. RNA pull down and RNA immunoprecipitation verified YTHDF2 was the reader of NEDD4. NEDD4 promoted the proliferation and chemoresistance of gemcitabine resistance cells. FTO knockdown markedly reduced RRM1 expression level in NEDD4 dependent manner, thus influence the chemosensitivity to gemcitabine in pancreatic cancer cells.

Conclusion: We found FTO regulated gemcitabine resistance in pancreatic cancer by demethylated NEDD4 RNA in m6a-dependent manner which then influenced the RRM1 expression level. Meanwhile, we identified FTO protein level can be upregulated by USP7.