Scientists discover new therapeutic targets for poor prognostic subtypes of ovarian cancer

The inactivating mutation of the ARID1A tumor suppressor gene is the genetic driver of OCCC.

"The goal of our research is to discover the molecular changes caused by ARID1A deletion, so that we can target them to achieve effective treatment of this devastating disease," Dr.

The endoplasmic reticulum (ER) is a cellular structure that monitors protein production and has a complex mechanism to deal with the stress caused by the accumulation of misfolded proteins

The IRE1a/XBP1 pathway is the main signaling pathway of the endoplasmic reticulum stress response

Zhang and colleagues found that ARID1A inhibits the IRE1a/XBP1 pathway.

"In some cases, the favorable mechanisms used by cancer cells also make them vulnerable because they become dependent on certain pathways," Zhang added

Importantly, this observation was confirmed in vivo, because B-I09 treatment reduced the tumor burden in arid1a inactivated ovarian tumor mouse model and improved survival

Therapeutic resistance allows cancer cells to escape the effects of single-drug therapy, and the combined strategy provides a solution to this major challenge

"Our results show that the pharmacological inhibition of the IRE1a/XBP1 pathway of the endoplasmic reticulum stress response, alone or in combination with HDAC6 inhibition, represents a potential treatment strategy for arid1a mutant cancers," said Joseph Zundell, who is Zhang A pre-doctoral trainee in the laboratory is also the first author of this paper

Journal Reference :

1. Joseph A.