Glioblastoma Cell Resistance to EGFR and MET Inhibition Can Be Overcome via Blockade of FGFR-SPRY2 Bypass Signaling

Day, Evan K.; Sosale, Nisha G.; Xiao, Aizhen; Zhong, Qing; Purow, Benjamin; Lazzara, Matthew J.

doi:10.1016/j.celrep.2020.02.014

Cited by 30 publications

(33 citation statements)

References 55 publications

(57 reference statements)

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“…The EGFR-independent pathway may maintain stimulation of the PI3K-AKT signaling pathway. We and others previously reported an impact of integrin or JAK signaling in glioma intracellular signaling 55 , 56 , and other receptor tyrosine kinases 57 – 60 may be involved. Clark et al 57 demonstrated a compensatory activation of EGFR-related family members (ERBB2 and ERBB3) that enabled glioma stem cell proliferation, suggesting that simultaneous blockade of multiple ERBB family members may be required for more efficacious GBM therapy.…”

Section: Discussionmentioning

confidence: 70%

EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide

et al. 2020

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Accumulating evidence suggests that glioma stem cells (GSCs), which are rare cells characterized by pluripotency and self-renewal ability, are responsible for glioblastoma (GBM) propagation, recurrence and resistance to therapies. Bone morphogenic proteins (BMPs) induce GSC differentiation, which leads to elimination of GSCs and sensitization of glioma to chemotherapeutics. Alterations in the epidermal growth factor receptor (EGFR) gene are detected in more than half of GBMs; however, the role of EGFR in the chemoresistance of GSCs remains unknown. Here, we examined whether EGFR signaling affects BMP4-induced differentiation of GSCs and their response to the alkylating drug temozolomide (TMZ). We show that BMP4 triggers the SMAD signaling cascade in GSCs independent of the EGFR level. BMP4 downregulated the levels of pluripotency markers (SOX2 and OLIG2) with a concomitant induction of an astrocytic marker (GFAP) and a neuronal marker (β-Tubulin III). However, GSCs with different EGFR levels responded differently to treatments. BMP4-induced differentiation did not enhance sensitivity to TMZ in EGFRlow GSCs, in contrast to EGFRhigh GSCs, which underwent apoptosis. We then identified differences in cell cycle regulation. In EGFRlow cells, BMP4-triggered G1 cell cycle arrest which was not detected in EGFRhigh cells. RNA-seq profiles further highlighted transcriptomic alterations and distinct processes characterizing EGFR-dependent responses in the course of BMP4-induced differentiation. We found that the control of BIM (the pro-apoptotic BCL-2 family protein) by the AKT/FOXO3a axis only operated in BMP4-differentiated EGFRhigh cells upon TMZ treatment.

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Section: Discussionmentioning

confidence: 70%

EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide

et al. 2020

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“…Direct repression of MAPKs MEK or ERK1/2 or the upstream activator Ras are associated with the emergence of resistance either by the reactivation of ERK1/2 through impaired repression or the activation of an alternative pathway [17] , [18] , [19] . One potential indirect repressor of ERK1/2 activation in tumor cells is dasatinib, a second-generation multitarget kinase inhibitor targeting both SRC and BCR-ABL kinases.…”

Section: Introductionmentioning

confidence: 99%

Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

et al. 2020

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Highlights Growth factor signaling causes sustained nuclear ERK1/2 activation. The SCR and BCR/ABL inhibitor dasatinib blocks ERK1/2 and represses cell invasion. EGF-stimulated cells may escape dasatinib inhibition of invasion through mesenchymal to amoeboid transition. Combined inhibition of SRC and Rho-kinase signaling is necessary to completely block EGF-induced invasion.

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“…Both the EGFR and FGFR signal transduction pathways are important in cancer, and the FGFR pathway is activated by EGFR-TKI treatment [ 11 ]. Therefore, the activation of the FGFR is likely to be another cause of resistance to EGFR-TKIs, and the combination of FGFR-TKIs and EGFR-TKIs is effective in glioblastoma and non-small cell lung cancer, as previously reported [ 42 , 43 ]. Since the FGFR mediates EGFR signaling, the efficacy of FGFR-TKIs in cancer treatment was investigated using C. elegans tumor models and lung cancer cell lines.…”

Section: Discussionmentioning

confidence: 74%

Rab8 and Rabin8-Mediated Tumor Formation by Hyperactivated EGFR Signaling via FGFR Signaling

Choi

Sung

Lee

et al. 2020

IJMS

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The epidermal growth factor receptor (EGFR) signaling is important for normal development, such as vulval development in Caenorhabditis elegans, and hyperactivation of the EGFR is often associated with cancer development. Our previous report demonstrated the multivulva (Muv) phenotype, a tumor model in C. elegans (jgIs25 strain) by engineering LET-23/EGFR with a TKI-resistant human EGFR T790-L858 mutant. Because Rab proteins regulate vesicle transport, which is important for receptor signaling, we screened the RNAi in the jgIs25 strain to find the Rabs critical for Muv formation. Herein, we show that rab-8 RNAi and the rab-8 (-/-) mutation effectively reduce Muv formation. We demonstrate that RABN-8, an ortholog of Rabin8, known as a GEF for Rab8, is also required for Muv formation by promoting the secretion of EGL-17/FGF from vulval precursor cells. In addition, FGFR inhibitors decreased Muv formation mediated by mutant EGFR. Our data suggest that Rab8 and Rabin8 mediate Muv formation through FGF secretion in the EGFR-TKI-resistant nematode model. Furthermore, FGFR-TKIs more effectively inhibit the growth of lung cancer cell lines in H1975 (EGFR T790M-L858R; EGFR-TKI-resistant) than H522 (wild-type EGFR) and H1650 (EGFR exon 19 deletion; EGFR-TKI-sensitive) cells, suggesting that FGFR-TKIs could be used to control cancers with EGFR-TKI-resistant mutations.

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Glioblastoma Cell Resistance to EGFR and MET Inhibition Can Be Overcome via Blockade of FGFR-SPRY2 Bypass Signaling

Cited by 30 publications

References 55 publications

EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide

EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide

Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

Rab8 and Rabin8-Mediated Tumor Formation by Hyperactivated EGFR Signaling via FGFR Signaling

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