Even though surgery is usually preformed with a curative intent, there are often local or distant colon cancer recurrences in many patients. As such, 5-fluorouracil (5-FU)-based systemic adjuvant chemotherapy has been applied in patients considered to be at high risk of recurrence, and has shown benefits in several different trials. Nonetheless, the role of chemotherapy in colon cancer is still debated, especially for stage II and III colon cancer patients. Importantly, the development of 5-FU resistance in some patients, resulting in an increased colon cancer therapy failure, has become more common.
In their study, titled “PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy” and published in Oncotarget, the team used tumor cells from colon cancer patients as well as animal models of this disease, to demonstrate that PAK6 is involved in the promotion of tumor progression and chemoresistance.
Upon analysis of stage II and III colon cancer patient’s tumor cells, researchers observed that the majority (70.75%) overexpressed PAK6, which could be used as an independent prognostic marker of survival and disease-free survival.
Importantly, upon 5-FU chemotherapeutic treatment, in vitro colon cancer cell lines began to overexpress PAK6. As such, the team proceeded to block this protein, which resulted in increased tumor cell death upon chemotherapeutic treatment. Importantly, in vivo models were consistent with the cellular results.
“Until now, no valid prognostic biomarkers for colon cancer chemotherapy have been established, although several potential molecular predictors of recurrence risk and chemotherapy benefit have been investigated”, the authors write in their study. “Our results indicate that a combination of PAK6 inhibition and 5-FU treatment results in significantly decreased survival in colon cancer cells, which can be restored by PAK6 expression. These findings highlight the potential role that PAK6 may play in chemoresistance and indicate that PAK6 could be an effective target for 5-FU sensitization in colon cancer, although further research is required to confirm our findings”, they further conclude.