Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer

Pan, Chun-Hao, Lyu, Yinghuan, Ghosh, Monisankar, Siraj, Md Afjalus, Tseng, Robert, Chaika, Nina V, Haley, John D, Khalvatifahlylani, Bahman, Tuveson, David A, Patel, Hardik D, Faruque, Muaz, Rajacharya, Girish H, Donnelly, Katie L, Leiton, Cindy V, Mejia Arbelaez, Carlos, Chen, Haoting, Chowdhury, Sumedha, Sarkar, Shayan, Delgado Coka, Lyanne, Roa-Peña, Lucia, Horowitz, Michael, Marchenko, Natalia, Singh, Pankaj K, Shroyer, Kenneth R, Escobar-Hoyos, Luisa F (March 2026) Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer. Cancer Research. OF1-OF16. ISSN 0008-5472

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Abstract

The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is highly lethal and therapy resistant. A better understanding of the underlying molecular mechanisms driving this aggressive tumor subtype is necessary for the development of effective therapies. Notably, upregulation of keratin 17 (K17) in cancer is associated with poor patient outcome and the basal-like PDAC subtype. Here, we identified a critical dependency of basal-like PDACs on de novo pyrimidine biosynthesis, driven by intra-mitochondrial K17. Mechanistically, K17 translocated into the mitochondrial intermembrane space via a mitochondrial localization sequence (MLS) recognized by the translocase of the outer mitochondrial membrane 20 (TOM20). In the mitochondria, K17 bound to and stabilized dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of de novo pyrimidine biosynthesis, by preventing its ubiquitination-mediated degradation. Blocking the entry of K17 into the mitochondria sensitized cancer cells to gemcitabine, a pyrimidine analog and standard chemotherapeutic agent. In animal studies, pharmacologic inhibition of DHODH combined with gemcitabine treatment decreased tumor growth and doubled survival in mice bearing K17⁺ but not K17⁻ PDAC. These findings define a mitochondrial role for K17 in driving pyrimidine biosynthesis and uncover a metabolic vulnerability in K17⁺ basal-like PDACs that can be therapeutically targeted.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A. Patel, Hardik
Communities:	CSHL labs > Beyaz lab CSHL labs > Tuveson lab CSHL Cancer Center Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	12 March 2026
Date Deposited:	17 Jun 2026 11:29
Last Modified:	17 Jun 2026 11:29
PMCID:	PMC13266344
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42224

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