Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. We previously reported keratin 17 (K17) as a novel negative prognostic and predictive biomarker, whose overexpression confers the resistance to chemotherapies. Here, we investigated the mechanisms of chemoresistance and tumor-specific vulnerabilities that can be exploited for targeted therapies for K17-expressing PDAC. Unbiased metabolomic studies in isogenic PDAC models identified several key metabolic pathways that are upregulated in the presence of K17. We demonstrate that K17 increases pyrimidine biosynthesis, a pathway that has been linked to chemoresistance. Patient dataset analysis revealed that K17 expression and enzymes involved in pyrimidine, but not purine, de novo biosynthesis is associated with shorter patient survival. Rescue experiments showed that deoxycytidine (dC) and deoxythymidine (dT) were sufficient to promote resistance to Gemcitabine (a dC analog) and 5-fluorouracil (a dT analog), respectively. Furthermore, K17-expressing cells were more sensitive to Brequinar, a specific inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine biosynthetic pathway. Targeting DHODH by small interfering RNA or by Brequinar with Gemcitabine synergistically inhibited the viability of K17-positive PDAC cells. Importantly, the combination of Gemcitabine and Brequinar significantly inhibited the growth of K17-expressing tumors and extended survival of mice bearing K17-expressing PDACs. Overall, we identified a novel pathway of chemoresistance and a metabolic target of which could lead to the development of a biomarker-based therapy for K17-expressing PDAC.

Keratin 17 modulates the immune topography of pancreatic cancer

“…To the best of our knowledge, this is the first study that aims to consolidate the histological subtype stratification with the tumoral microenvironment status to better understand tumor aggression and rationalize more personalized therapeutic strategies. We and others have shown that keratin 17 (K17) drives chemoresistance and is a prognostic and predictive biomarker of the most aggressive (basal) molecular subtype of PDAC [35,37,38,46,47]. K17 expression also impacts the immune response in several cancer types, including basal cell carcinoma, head and neck cancer [14,57,58], and cervical squamous cell carcinoma [5].…”