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Gurule et al. Cancer Drug Resist 2018;1:118-25 Cancer
DOI: 10.20517/cdr.2018.12 Drug Resistance

Opinion Open Access

Linking tyrosine kinase inhibitor-mediated
inflammation with normal epithelial cell homeostasis

and tumor therapeutic responses

Natalia J. Gurule, Lynn E. Heasley

Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Correspondence to: Natalia J. Gurule, Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus,
12801 E. 17th Ave., Aurora, CO 80045, USA. E-mail: natalia.gurule@ucdenver.edu
How to cite this article: Gurule NJ, Heasley LE. Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial
cell homeostasis and tumor therapeutic responses. Cancer Drug Resist 2018;1:118-25.
http://dx.doi.org/10.20517/cdr.2018.12
Received: 6 Jul 2018 First Decision: 1 Aug 2018 Revised: 16 Aug 2018 Accepted: 20 Aug 2018 Published: 19 Sep 2018

Science Editors: Elisa Giovannetti, Jose Antonio Rodriguez Copy Editor: Yuan-Li Wang Production Editor: Cai-Hong Wang

Abstract
Receptor tyrosine kinases (RTKs) bearing oncogenic mutations in EGFR, ALK and ROS1 occur in a significant subset
of lung adenocarcinomas. Tyrosine kinase inhibitors (TKIs) targeting tumor cells dependent on these oncogenic RTKs
yield tumor shrinkage, but also a variety of adverse events. Skin toxicities, hematological deficiencies, nausea, vomiting,
diarrhea, and headache are among the most common, with more acute and often fatal side effects such as liver failure
and interstitial lung disease occurring less frequently. In normal epithelia, RTKs regulate tissue homeostasis. For
example, EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling.
Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory
response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations.
Mechanistically, blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells
driven by this RTK. This innate immune response within the tumor microenvironment (TME) involves increased antigen
presentation and effector T cell recruitment that may participate in therapy response. This TKI-mediated release
of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs
with immune-oncology agents that rely on T-cell inflammation for efficacy. However, early clinical data indicate that
combination therapies enhance the frequency and magnitude of the more acute adverse events, especially pneumonitis,
hepatitis, and pulmonary fibrosis. Further preclinical studies to understand TKI mediated inflammation and crosstalk
between normal epithelial cells, cancer cells, and the TME are necessary to improve treatment regimens for patients with
RTK-driven carcinomas.

Keywords: Tyrosine kinase inhibitor, receptor tyrosine kinase, interferon, inflammation, tumor microenvironment,
epithelial tissue homeostasis
© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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