Diarrhea Induced by Small Molecule Tyrosine Kinase Inhibitors Compared With Chemotherapy: Potential Role of the Microbiome

Kate R Secombe, Ysabella Z A Van Sebille, Bronwen J Mayo, Janet K Coller, Rachel J Gibson, Joanne M Bowen, Kate R Secombe, Ysabella Z A Van Sebille, Bronwen J Mayo, Janet K Coller, Rachel J Gibson, Joanne M Bowen

Abstract

Small molecule receptor tyrosine kinase inhibitors (SM-TKIs) are among a group of targeted cancer therapies, intended to be more specific to cancer cells compared with treatments, such as chemotherapy, hence reducing adverse events. Unfortunately, many patients report high levels of diarrhea, the pathogenesis of which remains under investigation. In this article, we compare the current state of knowledge of the pathogenesis of chemotherapy-induced diarrhea (CID) in comparison to SM-TKI-induced diarrhea, and investigate how a similar research approach in both areas may be beneficial. To this end, we review evidence that both treatment modalities may interact with the gut microbiome, and as such the microbiome should be investigated for its ability to reduce the risk of diarrhea.

Keywords: chemotherapy; diarrhea; microbiome; supportive care; tyrosine kinase inhibitors.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Potential interactions of the gut microbiome with tyrosine kinase inhibitor (TKI) treatments leading to diarrhea. (A) Chemotherapy causes vast changes to the gut microbiome,, as well as activation of inflammatory pathways via pattern recognition receptors (PRRs), such as Toll-like receptor 4,, that lead to ulceration and eventual diarrhea. TKI treatment also leads to diarrhea, but the mechanism is not well understood. We propose that the gut microbiome may play a key role. (B) Long-term TKI treatment may lead to a dysbiotic microbiome. Additionally, direct inhibition of EGFRs or VEGFRs in the gut can lead to altered gut function (eg, changes in cell proliferation and capillary networks) that can alter microbial composition.- This could lead to similar inflammatory outcomes as in chemotherapy. (C) Alternatively, increased chloride secretion in the gut (causing diarrhea itself) could lead to a significant shift in the microbiome that may lead to additive effect on the diarrhea.,,

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