Involvement of tyrosine phosphatase PTPROt in acquired resistance to FGFR inhibitor therapy in colorectal cancer.

Authors

Shoichi Kitano, Hiroyuki Miyoshi, Takehito Yamamoto, Hiroyuki Matsubara, Tomonori Morimoto, Fumihiko Kakizaki, Kenji Kawada, Kazutaka Obama, Yoshiharu Sakai, Makoto Mark Taketo

Published in

Molecular cancer therapeutics. Jun 15, 2026. Epub Jun 15, 2026.

Abstract

The benefits of fibroblast growth factor receptor (FGFR) inhibitor therapy in several malignancies are often limited by the emergence of drug resistance. Recent studies have uncovered its molecular mechanisms, particularly in urothelial cancer and cholangiocarcinoma, but not yet in colorectal cancer (CRC). Here, we investigated FGFR inhibitor resistance mechanisms using patient-derived CRC stem-cell (SC) spheroids. To obtain FGFR inhibitor-resistant CRC-SC spheroid lines, we performed long-term in vitro treatment with FDA-approved pan-FGFR inhibitors, erdafitinib and futibatinib. The paired drug-resistant and parental spheroid stem cells were subjected to RNA-sequencing for mutational and transcriptional profiling. We examined the involvement of differentially expressed genes in resistance mechanisms by functional tests and CRISPR-mediated gene disruption. We established 7 FGFR inhibitor-resistant CRC-SC lines from 4 parental lines that responded well to FGFR inhibitors. All resistant lines showed EGFR mRNA upregulation and PTPRO mRNA downregulation, correlating with reduced sensitivities to the pan-FGFR inhibitors, erdafitinib and futibatinib. EGF stimulation of these lines induced MAPK and PI3K-AKT pathway activation more potently than that of their parental lines. Additionally, PTPRO gene disruption in the parental lines conferred resistance to erdafitinib and futibatinib by upregulating EGFR. Importantly, the combination treatment of resistant lines with an EGFR inhibitor erlotinib effectively suppressed the MAPK and PI3K-AKT signaling. In conclusion, Enhanced EGFR signaling, partly driven by PTPRO downregulation, was a key mechanism of acquired resistance to FGFR inhibitors in RAS/RAF wild-type CRC. The combination treatment with FGFR and EGFR inhibitors can be a promising strategy to overcome this resistance.

PMID:
42295205
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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