Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC

Gammelgaard, Kristine Raaby; Vad-Nielsen, Johan; Clement, Michelle Simone; Weiss, Simone; Daugaard, Tina Fuglsang; Dagnæs‐Hansen, Frederik; Meldgaard, Peter; Sørensen, Boe Sandahl; Nielsen, Anders Lade

doi:10.1016/j.tranon.2018.11.017

Cited by 23 publications

(17 citation statements)

References 30 publications

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“…Early functional drug tolerance to the therapy leads to the accumulation of a pool of persisting cells that, over time, can gain novel resistance mutations. 16,17 Drug tolerance may be facilitated by feedback activation of survival pathways, 16,[26][27][28] altered epigenetic states 29,30 or regulation by the microenvironment. 31,32 Several mechanisms of constitutive primary and secondary resistance have been identified in lung cancer, 33 but the molecular mechanisms underlying early drug tolerance to EGFR-TKI remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Targeting USP13‐mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non‐small cell lung cancer

Giron

Eggermont

Noeparast

et al. 2021

Intl Journal of Cancer

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In non‐small cell lung cancer (NSCLC), activating mutations in the epidermal growth factor receptor (EGFR) induce sensitivity to EGFR tyrosine kinase inhibitors. Despite impressive clinical responses, patients ultimately relapse as a reservoir of drug‐tolerant cells persist, which ultimately leads to acquired resistance mechanisms. We performed an unbiased high‐throughput siRNA screen to identify proteins that abrogate the response of EGFR‐mutant NSCLC to EGFR‐targeted therapy. The deubiquitinase USP13 was a top hit resulting from this screen. Targeting USP13 increases the sensitivity to EGFR inhibition with small molecules in vitro and in vivo. USP13 selectively stabilizes mutant EGFR in a peptidase‐independent manner by counteracting the action of members of the Cbl family of E3 ubiquitin ligases. We conclude that USP13 is a strong mutant EGFR‐specific cotarget that could improve the treatment efficacy of EGFR‐targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Targeting USP13‐mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non‐small cell lung cancer

Giron

Eggermont

Noeparast

et al. 2021

Intl Journal of Cancer

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“…Phospho-receptor-tyrosine-kinase arrays, detecting phosphorylation of 49 human receptor tyrosine kinases (RTKs), showed no activation of RTKs in the resistant cells (data not shown). We have previously noted that FGFR1 phosphorylation is not detected on these RTK arrays despite examining HCC827 cells with active FGFR1 signaling (20).…”

Section: Fgfr1 Is Involved In Met-tki Resistancementioning

confidence: 94%

Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

Clement¹,

Gammelgaard²,

Nielsen³

et al. 2020

Transl Lung Cancer Res

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Background: Tyrosine kinase inhibitor (TKI) resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC). MET amplification drives resistance to EGFR-TKIs in 5-20% of initially sensitive EGFR-mutated NSCLC patients, and combined treatment with EGFR-TKIs and MET-TKIs can overcome this resistance. Yet, inevitably MET-TKI resistance will also occur. Hence, knowledge on development of this sequential resistance is important for identifying the proper next step in treatment.Methods: To investigate sequential resistance to MET-TKI treatment, we established a two-step TKI resistance model in EGFR-mutated HCC827 cells with MET amplification-mediated erlotinib resistance.These cells were subsequently treated with increasing doses of the MET-TKIs capmatinib or crizotinib in combination with erlotinib to establish resistance.Results: In all the MET-TKI resistant cell lines, we systematically observed epithelial-to-mesenchymal transition (EMT) evident by decreased expression of E-cadherin and increased expression of vimentin and ZEB1. Furthermore, FGFR1 expression was increased in all MET-TKI resistant cell lines and four out of the six resistant cell lines had increased sensitivity to FGFR inhibition, indicating FGFR1-mediated bypass signaling.Conclusions: EMT is common in the development of sequential EGFR-TKI and MET-TKI resistance in NSCLC cells. Our findings contribute to the evidence of EMT as a common TKI resistance mechanism.

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“…Most studies on the involvement of FGF proteins in the development of drug resistance involve FGF1 and FGF2, while there are a few reports on the role of other FGFs in this process, including FGF4, FGF5, FGF9, FGF10, FGF13, and FGF19 [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Overexpression of FGF receptors in cancer cells has also been observed with a concomitant reduction in response to protein kinase inhibitors (including RTKs) or endocrine therapy ( Table 1 ) [ 39 , 45 , 46 , 47 , 48 , 49 , 50 ]. To investigate the involvement of FGF proteins and their receptors in the process of chemoresistance, particular attention has been paid to FGFR-dependent signaling pathways and their downstream targets, which can lead to deregulation of a number of biological processes, including apoptosis and metastasis.…”

Section: The Role Of Cell Signaling Pathways In the Development Of Anti-cancer Drug Resistancementioning

confidence: 99%

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Szymczyk

Sluzalska

Materla

et al. 2021

Cancers

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Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.

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Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC

Cited by 23 publications

References 30 publications

Targeting USP13‐mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non‐small cell lung cancer

Targeting USP13‐mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non‐small cell lung cancer

Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

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