Overall survival in EGFR mutated non-small-cell lung cancer patients treated with afatinib after EGFR TKI and resistant mechanisms upon disease progression

Wekken, Anthonie J. van der; Kuiper, J.; Saber, Aly; Terpstra, Miente Martijn; Wei, Jiacong; Hiltermann, T Jeroen N; Thunnissen, Erik; Heideman, Daniëlle A.M.; Timens, Wim; Schuuring, Ed; Kok, Klaas; Smit, Egbert F.; Berg, Anke van den; Groen, Harry J.M.

doi:10.1371/journal.pone.0182885

Cited by 22 publications

(14 citation statements)

References 52 publications

(41 reference statements)

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“…Our results show that EGFR loss leads to the resistance of renal cancer cells to cisplatin, HDAC inhibitors and TRAIL [30][31][32]. Several studies have shown that the EGFR status is associated with drug resistance in cancer [33][34][35]. According to our observations, disruption of overexpressed EGFR suppresses cancer cell growth, but ultimately leads to the reactivation of pERK and/or pAKT via an EGFR independent mechanism and drug resistance.…”

Section: Plos Onesupporting

confidence: 54%

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

et al. 2020

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Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR-/cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/ M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/ Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma.

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Section: Plos Onesupporting

confidence: 54%

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

et al. 2020

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“…The bioinformatics pipeline of the UMCG genome facility was used for data analysis, as described previously [ 26 , 27 ]. Briefly, reads were aligned to the human 1000 genomes reference based on the GRCh37 build using BWA 5.9rc.…”

Section: Methodsmentioning

confidence: 99%

Mutational Evolution in Relapsed Diffuse Large B-Cell Lymphoma

Nijland

Seitz

Terpstra

et al. 2018

Cancers

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Current genomic models in diffuse large B-cell lymphoma (DLBCL) are based on single tumor biopsies, which might underestimate heterogeneity. Data on mutational evolution largely remains unknown. An exploratory study using whole exome sequencing on paired (primary and relapse) formalin fixed paraffin embedded DLBCL biopsies (n = 14) of 6 patients was performed to globally assess the mutational evolution and to identify gene mutations specific for relapse samples from patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. A minority of the mutations detected in the primary sample (median 7.6%, range 4.8–66.2%) could not be detected in the matching relapse sample. Relapsed DLBCL samples showed a mild increase of mutations (median 12.5%, range 9.4–87.6%) as compared to primary tumor biopsies. We identified 264 genes possibly related to therapy resistance, including tyrosine kinases (n = 18), (transmembrane) glycoproteins (n = 73), and genes involved in the JAK-STAT pathway (n = 7). Among the potentially resistance related genes were PIM1, SOCS1, and MYC, which have been reported to convey a risk for treatment failure. In conclusion, we show modest temporal heterogeneity between paired tumor samples with the acquisition of new mutations and identification of genes possibly related to therapy resistance. The mutational evolution could have implications for treatment decisions and development of novel targeted drugs.

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“…Three generations of EGFR-TKIs were developed. The first generation of EGFR-TKIs such as erlotinib or gefitinib, exhibit resistance after several months of treatment in patients with EGFR-activating mutations, especially in NSCLC patients [ 60 ]. The EGFR T790M mutation confers resistance to gefitinib via blockade of drug binding [ 61 ].…”

Section: Vegfr-tkis and Other Signalling Pathwaysmentioning

confidence: 99%

Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma

et al. 2018

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel–Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy. VEGF monoclonal antibodies and VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are the main drugs used in anti-angiogenic therapy. However, crosstalk between VEGFR and other tyrosine kinase or downstream pathways produce resistance to TKI treatment, and the multi-target inhibitors, HIF inhibitors or combination strategies are promising strategies for mRCC. HIFs are upstream of the crosstalk between the growth factors, and these factors may regulate the expression of VEGR, EGF, PDGF and other growth factors. The frequent VHL loss in ccRCC increases HIF expression, and HIFs may be an ideal candidate to overcome the TKI resistance. The combination of HIF inhibitors and immune checkpoint inhibitors is also anticipated. Various clinical trials of programmed cell death protein 1 inhibitors are planned. The present study reviews the effects of current and potential TKIs on mRCC, with a focus on VEGF/VEGFR and other targets for mRCC therapy.

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Overall survival in EGFR mutated non-small-cell lung cancer patients treated with afatinib after EGFR TKI and resistant mechanisms upon disease progression

Cited by 22 publications

References 52 publications

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

Mutational Evolution in Relapsed Diffuse Large B-Cell Lymphoma

Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma

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