# Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers

## TL;DR

This study explores how anti-angiogenic tyrosine kinase inhibitors cause anemia in cancer patients by damaging bone marrow and blocking red blood cell development.

## Contribution

The study reveals that sunitinib causes anemia through both vascular damage in the bone marrow and autophagy inhibition in red blood cell precursors.

## Key findings

- Anti-angiogenic TKIs harm normal endothelial cells, leading to tissue toxicity.
- Sunitinib causes anemia by destroying bone marrow vessels and reducing erythropoietin availability.
- Sunitinib uniquely inhibits autophagy in erythroid progenitors, worsening anemia.

## Abstract

Anti-angiogenic tyrosine kinase inhibitors (TKIs) have become major drugs for the treatment of various cancer types, but with an overall high incidence of severe toxicities, particularly haematological toxicities including severe anemia.

We treated C57BL6 mice continuously by gavage for 14 days with either sunitinib, pazopanib, or axitinib. In this study, we set out to decipher the pathophysiological mechanisms of anti-angiogenic TKI haematological toxicity.

We demonstrated that anti-angiogenic TKIs induced a broad range of toxic effects on normal tissues through a cytotoxic effect on normal endothelial cells. Haematological toxicities were particulary marked with sunitinib. Sunitinib-induced hypoxia through the destruction of normal vessels in the bone marrow mainly affected erythrocyte and myeloid lineages, and this was associated with a blockage in erythrocyte maturation. Althought sunitinib-induced anemia was associated with an adaptative response to systemic hypoxia, we demonstrated that erythropoietin (EPO) concentrations in the total bone marrow of sunitinib-treated mice were significantly lower than in untreated mice. This is coherent with the destruction of microvessels in the bone marrow under sunitinib treatment, preventing circulating EPO from reaching the bone marrow at relevant concentrations. However, we demonstrated an additional effect specific to sunitinib that induced autophagy flux inhibition in erythroid progenitors, with a blockage of erythrocyte maturation, leading to more severe anemia.

We deciphered the pathophysiology of anti-angiogenic TKI-induced anemia, which we observed to be mainly linked to a direct effect on normal bone-marrow vessels and to autophagy flux inhibition in erythroid progenitors under sunitinib.

The online version contains supplementary material available at 10.1186/s40164-025-00640-9.