Chemoresistance is a serious problem for many cancer therapies. Solutions to this problem are harder to come by than the medicines themselves, but a team from Sapienza University in Rome may have an answer for colorectal cancer.
Colorectal cancer is known for developing chemoresistance. However, a recent study pointed to a signaling pathway, the Hedgehog-GLI pathway, as a critical player in developing that resistance. This pathway is typically involved in regulating cell differentiation in early development but has also been linked to tumor development when dysregulated. The team decided to conduct a new study to determine how the Hedgehog- GLI pathway is involved in colorectal cancer’s chemoresistance.
The study began by examining the protein GLI, the genetic regulator involved in the Hedgehog-GLI pathway, in colorectal cancer cells after treatment with the first-line chemotherapies. The drugs both activated and upregulated GLI, and increased cancer cell death - albeit alongside a small increase to growth at low doses. Using a GLI inhibitor alongside the chemotherapy drugs suppressed this growth effect and increased the chemotherapies’ anti-cancer activity. So they knew that inhibiting GLI prevented GLI dependent growth, but how did it do it?
The team knew that a particular family of transporters, ATP-binding cassettes (ABC) transporters, were often involved in drug resistance and may play a role in Hedgehog-GLI mediated chemoresistance. They identified several down-regulated members during GLI inhibition and found that GLI overexpression coincided with the ABC transporters’ overexpression as well. This effectively linked the Hedgehog-GLI pathway to ABC transporters, which are known to facilitate chemoresistance in cancers.
This study’s data supports the idea that Hedgehog-GLI mediated chemoresistance is given by GLIs activation of certain ABC-transporters. This pathway has already been the target of several therapy studies, but the team notes that so far, many have ended poorly. However, this new information will assist with future studies by providing a viable target, GLI.
The team concludes, “Indeed, our results indicate that the addition of GLI targeting drugs to CRC treatment strategies is a therapeutic option that could prevent the onset of chemoresistance.”