Research Perspectives:

Pancreatic cancer driver mutations are targetable through distant alternative RNA splicing dependencies

Ryan R. Kawalerski, Steven D. Leach and Luisa F. Escobar-Hoyos _

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Oncotarget. 2021; 12:525-533. https://doi.org/10.18632/oncotarget.27901

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Ryan R. Kawalerski1, Steven D. Leach2 and Luisa F. Escobar-Hoyos3,4,5

1 Medical Scientist Training Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

2 Departments of Molecular and Systems Biology, Surgery, and Medicine, Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Lebanon, NH 03766, USA

3 Department of Therapeutic Radiology, Yale University, New Haven, CT 06513, USA

4 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06513, USA

5 Department of Pathology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA

Correspondence to:

Luisa F. Escobar-Hoyos,email: [email protected]

Keywords: pancreatic cancer; RNA splicing; targeted therapy; KRAS; TP53

Received: January 20, 2021     Accepted: February 03, 2021     Published: March 16, 2021

Copyright: © 2021 Kawalerski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, has one of the highest case fatality rates of all known solid malignancies. Over the past decade, several landmark studies have established mutations in KRAS and TP53 as the predominant drivers of PDAC pathogenesis and therapeutic resistance, though treatment options for PDACs and other tumors with these mutations remain extremely limited. Hampered by late tumor discovery and diagnosis, clinicians are often faced with using aggressive and non-specific chemotherapies to treat advanced disease. Clinically meaningful responses to targeted therapy are often limited to the minority of patients with susceptible PDACs, and immunotherapies have routinely encountered roadblocks in effective activation of tumor-infiltrating immune cells. Alternative RNA splicing (ARS) has recently gained traction in the PDAC literature as a field from which we may better understand and treat complex mechanisms of PDAC initiation, progression, and therapeutic resistance. Here, we review PDAC pathogenesis as it relates to fundamental ARS biology, with an extension to implications for PDAC patient clinical management.

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