Co-dependency for MET and FGFR1 in basal triple-negative breast cancers
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Vanessa Y C Sung1,2, Jennifer F Knight1, Radia M Johnson1
1Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Abstract:
Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks both effective patient stratification strategies and therapeutic targets. Whilst elevated levels of the MET receptor tyrosine kinase are associated with TNBCs and predict poor clinical outcome, the functional role of MET in TNBC is still poorly understood. In this study, we utilise an established Met-dependent transgenic mouse model of TNBC, human cell lines and patient-derived xenografts to investigate the role of MET in TNBC tumorigenesis. We find that in TNBCs with mesenchymal signatures, MET participates in a compensatory interplay with FGFR1 to regulate tumour-initiating cells (TICs). We demonstrate a requirement for the scaffold protein FRS2 downstream from both Met and FGFR1 and find that dual inhibition of MET and FGFR1 signalling results in TIC depletion, hindering tumour progression. Importantly, basal breast cancers that display elevated MET and FGFR1 signatures are associated with poor relapse-free survival. Our results support a role for MET and FGFR1 as potential co-targets for anti-TIC therapies in TNBC.
Insights
Targeting MET and FGFR1 in triple-negative breast cancer (TNBC) may deplete tumor-initiating cells. This study reveals MET and FGFR1 as potential co-targets for novel anti-cancer therapies in TNBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) is a heterogeneous subtype lacking effective therapeutic targets.
- Elevated MET receptor tyrosine kinase levels correlate with poor outcomes in TNBC, but its function remains unclear.
Purpose of the Study:
- To investigate the role of MET in triple-negative breast cancer tumorigenesis.
- To explore potential therapeutic strategies targeting MET and related signaling pathways.
Main Methods:
- Utilized a Met-dependent transgenic mouse model of TNBC.
- Employed human cell lines and patient-derived xenografts.
- Investigated the interplay between MET, FGFR1, and the scaffold protein FRS2.
Main Results:
- MET engages in compensatory signaling with FGFR1 to regulate tumor-initiating cells (TICs) in mesenchymal TNBC.
- FRS2 is a crucial downstream mediator for both MET and FGFR1.
- Dual inhibition of MET and FGFR1 signaling led to TIC depletion and impaired tumor progression.
- Elevated MET and FGFR1 signatures in basal breast cancers are linked to poor relapse-free survival.
Conclusions:
- MET and FGFR1 play a significant role in TNBC tumorigenesis by regulating TICs.
- Dual targeting of MET and FGFR1 shows promise for anti-TIC therapies in TNBC.
- These findings identify MET and FGFR1 as potential co-targets for improving TNBC treatment outcomes.
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