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01-10-2021 | NSCLC | PRECLINICAL STUDIES

FGFR leads to sustained activation of STAT3 to mediate resistance to EGFR-TKIs treatment

Authors: Xiaoping Song, Wei Tang, Hui Peng, Xin Qi, Jing Li

Published in: Investigational New Drugs | Issue 5/2021

Summary

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to great advances in the treatment of non-small cell lung cancer (NSCLC), but the emergence of drug resistance severely limits their clinical use. Thus, elucidation of the mechanism underlying resistance to EGFR-TKIs is of great importance. In our study, sustained activation of STAT3 was confirmed to be involved in resistance to EGFR-TKIs, and this resistance occurred regardless of exposure time, EGFR-TKIs type, and even cancer cell type. Mechanistically, the sustained activation of STAT3 was not related to gp130/JAK signalling pathway or HER2/EGFR heterodimer formation, while related to the expression and activation levels of STAT3. Furthermore, FGFR was shown to bind more strongly to STAT3 after gefitinib treatment, and the inhibition of FGFR reduced the phosphorylation of STAT3, thereby counteracting the effects of EGFR-TKIs and resulting in the synergistic inhibition of cancer cell proliferation. Taken together, the FGFR/STAT3 axis mediates the sustained activation of STAT3 upon EGFR-TKI treatment. This finding elucidates a new mechanism underlying drug resistance to EGFR-TKIs that the FGFR/STAT3 axis mediates the sustained activation of STAT3, providing theoretical support for considering the combination of TKIs and FGFR inhibitors in clinical cancer treatment.

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Title: FGFR leads to sustained activation of STAT3 to mediate resistance to EGFR-TKIs treatment
Authors: Xiaoping Song
Wei Tang
Hui Peng
Xin Qi
Jing Li
Publication date: 01-10-2021
Publisher: Springer US
Keywords: NSCLC
NSCLC
Erlotinib
Gefitinib
Published in: Investigational New Drugs / Issue 5/2021
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-021-01061-1

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