Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses.

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 (ILD) 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 (IFN) 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 (IO) 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.

SUBMITTER: Gurule NJ 

PROVIDER: S-EPMC6333470 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature