Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells

EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased fibroblast growth factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models. We show that while combined EGFR-TKI and FGFR inhibition showed some efficacy, simultaneous inhibition of FGFR and Akt or PI3K induced superior synergistic growth inhibition of FGFR1-overexpressing EGFR-TKI-resistant NSCLC cells. This effect was confirmed in vivo. Only dual FGFR and Akt inhibition completely blocked the resistance-mediating signaling pathways downstream of Akt. Further, increased FGFR1 expression was associated with significantly lower PFS in EGFR-TKI-treated NSCLC patients, and increased FGFR1 were demonstrated in a few post- vs. pre-EGFR-TKI treatment clinical biopsies. The superior therapeutic benefit of combining FGFR and Akt inhibitors provide the rationale for clinical trials of this strategy.

Eya1-dependent homeostasis of morphogenetic territories during collective cell migration

SUMMARYTissue remodeling presents an enormous challenge to the stability of intercellular signaling domains. Here we investigate this issue during the development of the posterior lateral line in zebrafish. We find that the transcriptional co-activator and phosphatase Eya1, mutated in the branchio-oto-renal syndrome in humans, is essential for the homeostasis of the Wnt/β-catenin and FGF morphogenetic domains during the collective migration of lateral-line primordial cells. Loss of Eya1 strongly diminishes the expression of Dkk1, expanding Wnt/β-catenin activity in the primordium, which in turn abrogates FGFR1 expression. Deficits in Eya1 also abolishes the expression of the chemokine receptor CXCR7b, disrupting primordium migration. These results reinforce the concept that morphogenetic domains in dynamically remodeling tissues are formed by cellular states maintained by continuous signaling.

FGFR1 Is Associated With Tamoxifen Resistance and Poor Prognosis of ER-Positive Breast Cancers by Suppressing ER Protein Expression

Fibroblast growth factor receptor 1 (FGFR1) is widely recognized as a key player in mammary carcinogenesis and associated with the prognosis and therapeutic response of breast cancers. With the aim of investigating the correlation between FGFR1 expression and estrogen receptor (ER) and exploring the effect of FGFR1 on endocrine therapy response and ER+ breast cancer prognosis, we examined the FGFR1 protein expression among 184 ER-positive breast cancers by the immunohistochemistry (IHC) method, analyzed the association between FGFR1 expression and disease characters using the Pearson’s chi-square test, and assessed the prognostic role of FGFR1 among breast cancers using Cox regression and Kaplan-Meier analyses. Moreover, in vitro assays were conducted to confirm the correlation between FGFR1 and ER expression and investigate the effect of FGFR1 on tamoxifen (TAM) sensitivity in ER+ breast cancer. The results showed that ER expression was negatively correlated with FGFR1 expression ( P = 0.011, r = -0.221). Moreover, FGFR1 expression was one of the prognostic factors of ER-positive breast cancer (OR = 1.974, 95% CI = 1.043-3.633), and high FGFR1 expression was correlated with decreased breast cancer overall survival. In addition, knocking down FGFR1 inhibited cell proliferation and enhanced TAM sensitivity in TAM-resistant cells. In conclusion, we found that there was a significant negative correlation between FGFR1 and ER levels in ER+ breast cancers, high FGFR1 protein expression was associated with poor breast cancer prognosis, down-regulating FGFR1 could elevate ER expression and is associated with enhanced TAM sensitivity in ER+ breast cancers.

Actomyosin and the MRTF-SRF pathway downregulate FGFR1 in mesenchymal stromal cells

Both biological and mechanical signals are known to influence cell proliferation. However, biological signals are mostly studied in two-dimensions (2D) and the interplay between these different pathways is largely unstudied. Here, we investigated the influence of the cell culture environment on the response to bFGF, a widely studied and important proliferation growth factor. We observed that human mesenchymal stromal cells (hMSCs), but not fibroblasts, lose the ability to respond to soluble or covalently bound bFGF when cultured on microfibrillar substrates. This behavior correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates. Inhibition of actomyosin or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 cells. To our knowledge, this is the first time FGFR1 expression is shown to be regulated through a mechanosensitive pathway in hMSCs. These results add to the sparse literature on FGFR1 regulation and potentially aid designing tissue engineering constructs that better control cell proliferation.

circITGA7 Functions as an Oncogene by Sponging miR-198 and Upregulating FGFR1 Expression in Thyroid Cancer

Background. Emerging evidence has indicated that circular RNAs (circRNAs), recognized as functional noncoding transcripts in eukaryotic cells, may be involved in regulating many physiological or pathological processes. However, the regulation and function of circular RNA circITGA7 in thyroid cancer (TC) remains unknown. Methods. In this study, we found that circITGA7 is upregulated in TC cell lines. We then performed functional analyses in the cell lines to support clinical findings. Mechanistically, we demonstrated that circITGA7 can directly bind to miR-198 and reduce the inhibition effect of miR-198 on target FGFR1 expression. Results. We reported an upregulation of circITGA7 in patients with TC. Silencing of circITGA7 inhibits metastasis and proliferation of TC cell lines in vitro. In addition, in the TC cell lines, the knockdown of circITGA7 or overexpression of miR-198 significantly suppressed FGFR1 levels. Mechanistically, we found that circITGA7 acts as miR-198 competitive endogenous RNA (ceRNA) to regulate FGFR1 expression. Conclusions. In summary, circRNA circITGA7 may play a regulatory role in TC and may be a potential marker for TC diagnosis or progression.

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Controlling basic fibroblast growth factor (bFGF) signaling is important for both tissue-engineering purposes, controlling proliferation and differentiation potential, and for cancer biology, influencing tumor progression and metastasis. Here, we observed that human mesenchymal stromal cells (hMSCs) no longer responded to soluble or covalently bound bFGF when cultured on microfibrillar substrates, while fibroblasts did. This correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates, compared to hMSCs on conventional tissue culture plastic (TCP). hMSCs also expressed less SRF on ESP scaffolds, compared to TCP, while fibroblasts maintained high FGFR1 and SRF expression. Inhibition of actin-myosin tension or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 osteosarcoma cells. This downregulation was functional, as hMSCs became irresponsive to bFGF in the presence of MRTF/SRF inhibitor. Together, our data show that hMSCs, but not fibroblasts, are irresponsive to bFGF when cultured on microfibrillar susbtrates by downregulation of FGFR1 through the MRTF/SRF pathway. This is the first time FGFR1 expression has been shown to be mechanosensitive and adds to the sparse literature on FGFR1 regulation. These results could open up new targets for cancer treatments and could aid designing tissue engineering constructs that better control cell proliferation.