FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor

Azuma, Koichi; Kawahara, Akihiko; Sonoda, Kahori; Nakashima, Kenichiro; Tashiro, Kousuke; Watari, Kosuke; Izumi, Hiroto; Kage, Masayoshi; Kuwano, Michihiko; Ono, Masahiro; Hoshino, Tomoaki

doi:10.18632/oncotarget.1866

Cited by 100 publications

(100 citation statements)

References 41 publications

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“…Although several mechanisms of resistance to second‐generation EGFR‐TKI including afatinib and dacomitinib have been identified in preclinical models, such mechanisms other than the T790M mutation have rarely been detected in clinical samples. With the use of NGS, we examined genetic alterations in tumor or plasma samples obtained from 25 patients at the time of systemic PD development during afatinib treatment.…”

Section: Discussionmentioning

confidence: 99%

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Exploration of resistance mechanisms for epidermal growth factor receptor‐tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next‐generation sequencing

et al. 2018

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Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance‐conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non‐small‐cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next‐generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M—including copy number gain of NRAS or MET—were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression‐free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR‐TKI treatment.

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Section: Discussionmentioning

confidence: 99%

“…Although several mechanisms of resistance to second-generation EGFR-TKI including afatinib and dacomitinib have been identified in preclinical models, [32][33][34][35] such mechanisms other than the T790M mu- Figure 2).…”

Section: Activating Mutation/ Control (%) T790m/control (%) T/a (%)mentioning

confidence: 99%

Exploration of resistance mechanisms for epidermal growth factor receptor‐tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next‐generation sequencing

et al. 2018

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“…More recently, a different group analyzed the EGFR TKI mechanism of resistance in NSCLC cell lines and they found a FGFR activation (FGF2 and FGFR1 were upregulated). The treatment inhibiting both pathways (EGFR and FGFR) improved the efficacy and might be a potential strategy to enhance antitumor activity (Azuma et al, 2014). In a group of 132 patients with NSCLC treated with an EGFR TKI, an alteration in FGFR1-3 has been found more frequently in the non-responders compared to responders (Lim et al, 2016a;Lim et al, 2016b).…”

Section: Resistance To Therapiesmentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

179

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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“…Along these lines, FGFR has previously been suggested as a mechanism of resistance to Her2 and other targeted molecular therapies [9, 16, 17]. Given these previous findings we sought to address the hypothesis that FGFR functions as a driver of EMT-associated drug resistance.…”

Section: Introductionmentioning

confidence: 97%

FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition

2016

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An emerging characteristic of drug resistance in cancer is the induction of epithelial-mesenchymal transition (EMT). However, the mechanisms of EMT-mediated drug resistance remain poorly defined. Therefore, we conducted long-term treatments of human epidermal growth factor receptor-2 (Her2)-transformed breast cancer cells with either the EGFR/Her2 kinase inhibitor, Lapatinib or TGF-β, a known physiological inducer of EMT. Both of these treatment regimes resulted in robust EMT phenotypes, but upon withdrawal a subpopulation of TGF-β induced cells readily underwent mesenchymal-epithelial transition, where as Lapatinib-induced cells failed to reestablish an epithelial population. The mesenchymal population that remained following TGF-β stimulation and withdrawal was quickly selected for during subsequent Lapatinib treatment, manifesting in inherent drug resistance. The Nanostring cancer progression gene panel revealed a dramatic upregulation of fibroblast growth factor receptor 1 (FGFR1) and its cognate ligand FGF2 in both acquired and inherent resistance. Mechanistically, FGF:Erk1/2 signaling functions to stabilize the EMT transcription factor Twist and thus maintain the mesenchymal and drug resistant phenotype. Finally, Lapatinib resistant cells could be readily eliminated using recently characterized covalent inhibitors of FGFR. Overall our data demonstrate that next-generation targeting of FGFR can be used in combination with Her2-targeted therapies to overcome resistance in this breast cancer subtype.

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FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor

Cited by 100 publications

References 41 publications

Exploration of resistance mechanisms for epidermal growth factor receptor‐tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next‐generation sequencing

Exploration of resistance mechanisms for epidermal growth factor receptor‐tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next‐generation sequencing

FGFR a promising druggable target in cancer: Molecular biology and new drugs

FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition

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