scholarly journals Effective Tyrosine Kinase Inhibitors result in the intracellular accumulation of EGFR and allows response prediction in patients

2019 ◽  
Author(s):  
Maurice de Wit ◽  
Ya Gao ◽  
Darlene Mercieca ◽  
Iris de Heer ◽  
Bart Valkenburg ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Conformational Changes ◽  
Clinical Benefit ◽  
Kinase Inhibitors ◽  
Response Prediction ◽  
Egfr Mutations ◽  
Tumor Type ◽  
Intracellular Accumulation ◽  
Egfr Tkis

AbstractClinical responses to EGFR tyrosine kinase inhibitors are restricted only to tumors harboring specific activating mutations and even then, not all tyrosine kinase inhibitors provide clinical benefit. We here show that the addition of EGFR-TKIs results in a strong and rapid intracellular accumulation of the protein. However, this accumulation was observed only in the context of a combination of a TKI-sensitive mutation with a clinically effective TKI: TKI-insensitive mutations did not show this accumulation nor did clinically ineffective TKIs induce accumulation. All TKIs effectively inhibited EGFR phosphorylation and downstream pathway activation, irrespective of the mutation present in EGFR. The discrepancy between molecular activity of TKIs and their efficacy in patients therefore is mimicked by the mutation- and TKI-specificity of intracellular accumulation. Using this intracellular accumulation as assay, we were able to predict response to gefitinib in a panel of cell-lines (harboring different EGFR mutations) and predicted clinical benefit to EGFR TKIs on a cohort of unselected pulmonary adenocarcinoma patients (hazard ratio 0.21, P=0.0004). Even in patients harboring rare mutations with unknown TKI-sensitivity, intracellular accumulation was predictive of the clinical response. The intracellular accumulation depended on a continued presence of TKI indicating that TKIs exert a continued effect on the protein even after its dephosphorylation. It is therefore possible that accumulation is caused by conformational changes induced by both the mutation and the TKI and this change induces a block in intracellular trafficking. Interestingly, intracellular accumulation was observed independent of the genetic background of the cell, indicating that accumulation is almost entirely dictated by the combination of mutation and TKI. Our results therefore suggest that TKI-sensitivity is tumor-type independent.

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

Preliminary analysis of biomarkers in plasma by SELDI to predict the response to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7189-7189
Author(s):  
L. Zhang ◽  
L. Ning ◽  
X. Zhang ◽  
Z. Q. Pan ◽  
X. Wang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Training Set ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr Tkis ◽  
Tof Ms ◽  
Testing Set

7189 Background: The identification of NSCLC patients who are most likely to respond to EGFR tyrosine kinase inhibitors (TKIs) have been investigated intensively. Although screenings for EGFR mutation and gene copy number are promising, these tests are not yet widely available. New predictor markers are urgently needed. The objective of this study was to identify proteomic markers in plasma to predict benefits for patients treated with EGFR TKIs. Methods: Proteomic spectra derived from plasma samples from EGFR TKIs-responsive patients and non-responsive patients were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). These proteomic spectra (WCX2 chips, Ciphergen Biosystems, Inc.) were then analyzed by comparing protein profiles in different response groups (PR Vs PD, training set). Another group of patients treaded with EGFR TKIs will be serving as testing set to validate the result of training set. Results: Totally, fifty-four advanced NSCLC patients were included in this study. All patients were treated with single agent of gefitinib or erlotinib. Twenty-nine patients were included in training set of this study. All were suitable for response evaluation. Ten patients (34.5%) were PR, 8 (27.6%) were SD, and 11 (37.9%) were progressive disease (PD). Total six significant protein peaks were significant (m/z 4288, 4595, 9191, 9349, 9397, and 9563) between PR group and PD group (table). Another twenty-five patients were included for testing set. Analyzing of testing set is still going on. Table shows PR and PD patients’ plasma comparison on WCX2 chips. Conclusions: This preliminary “training” set of spectra that uses SELDI-TOF MS technology found that six protein peaks seemed to be very important biomarkers to predict the response to gefitinib. Prospective tests to confirm these proteins and peptides will be present at this meeting. These results are promising for identifying new biomarkers of EGFR TKIs with SELDI. [Table: see text] No significant financial relationships to disclose.

Mutational analysis of EGFR and KIT in thymic epithelial tumor

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18049-18049
Author(s):  
K. Yoh ◽  
Y. Nishiwaki ◽  
G. Ishii ◽  
K. Goto ◽  
K. Kubota ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Thymic Carcinoma ◽  
Kinase Inhibitors ◽  
Mutational Analysis ◽  
Direct Sequencing ◽  
Egfr Mutations ◽  
Epithelial Tumor ◽  
Thymic Epithelial Tumor ◽  
Number Of Patients

18049 Background: Thymic epithelial tumor has been reported to express the epidermal growth factor receptor (EGFR), and thymic carcinoma has recently been described to have overexpression of KIT. We investigated the prevalence of EGFR and KIT mutations in patients with thymoma and thymic carcinoma to explore the potential for a targeted therapy with tyrosine kinase inhibitors. Methods: Genomic DNA was isolated from 41 paraffin-embedded tumor samples including 24 thymoma and 17 thymic carcinoma. EGFR mutations in exons 18, 19 and 21, and KIT mutations in exons 9, 11, 13 and 17, were analyzed by PCR and direct sequencing. Protein expressions of EGFR and KIT were also evaluated by immunohistochemistry. Results: We detected the EGFR mutation in 2 of 20 thymoma, but none of thymic carcinoma had mutation. All of the detected EGFR mutations were missense mutations in exon 21 (L858R and G863D, respectively). Expression of EGFR was seen in 71% of thymoma and 53% of thymic carcinoma. On mutational analysis of KIT, only one thymic carcinoma displayed a missense mutation in exon 11 (L576P). Expression of KIT was observed in 88% of thymic carcinoma and 0% of thymoma. Conclusions: Our findings indicate that a small number of patients with thymic epithelial tumor exhibit somatic mutations of EGFR or KIT although expressions of EGFR or KIT are present frequently in thymic epithelial tumor. Further investigations are warranted to determine their susceptibility to tyrosine kinase inhibitors in the treatment of thymoma and thymic carcinoma with EGFR or KIT mutations. No significant financial relationships to disclose.

CtDNA assay to detect EGFR mutations and mechanisms of resistance to EGFR tyrosine kinase inhibitors.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e23042-e23042
Author(s):  
Lyudmila Bazhenova ◽  
Satya Das ◽  
Sandip Pravin Patel ◽  
Lyle Arnold ◽  
Veena M. Singh
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egfr Mutations ◽  
Mechanisms Of Resistance ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

Prospective study for usefulness of circulating-free DNA on prediction of third generation EGFR tyrosine kinase inhibitors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21510-e21510
Author(s):  
Hironori Yoshida ◽  
Chiho Nakashima ◽  
Naohisa Matsumoto ◽  
Kentaro Iwanaga ◽  
Noriyuki Ebi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Disease Progression ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egfr Mutations ◽  
Plasma Samples ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr T790m

e21510 Background: Most non-small lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations develop resistance when exposed to EGFR-tyrosine kinase inhibitors (TKIs). T790M develops in about half of patients treated with TKI and can be detected by tumor tissue and cfDNA hotspot tests. However, co-occurring mutations at other loci may impact efficacy. We conducted a prospective, multi-center, observational study to assess the detection rates and predictive values of plasma-based EGFR T790M detection methods for Japanese NSCLC patients treated with osimertinib. Methods: NSCLC patients with tumor EGFR mutations and disease progression after treatment with 1st- or 2nd-generation EGFR-TKI were enrolled. Plasma was collected at the time of clinical disease progression, before osimertinib treatment. The collected plasma was tested for EGFR T90M by in-house plasma MBP-QP and ddPCR assays and compared to clinically tested cobas (Roche) results (including tissue, plasma). The primary endpoint was to demonstrate comparability of our MBP-QP system to cobas using plasma-based EGFR T790M detection to predict the therapeuitic effect of osimertinib via objective response rate (ORR) and disease control rate (DCR). As an exploratory analysis, we used Guardant360 to retrospectively test available banked plasma samples collected describe time points. Results: From Feb 2017 to Jan 2019, 145 patients enrolled. T790M was detected by cobas in 57 cases (44 tissue, 16 plasma, 3 both). ORR and DCR in plasma cobas-positive cases were 62.5% and 81.3%, respectively. MBP-QP found T790M in 9 patients with ORR and DCR 66.7% and 77.8%. ddPCR found 17 cases with ORR and DCR 70.6% and 82.4%. ORR was not correlated to AF. In plasma samples from 54 patients, Guardant360 detected T790M in 57%. Co-occurring alterations such as amplification or minor mutations in EGFR or other genes such as TP53 did not impact ORR, but in the group with poor response to osimertinib, the number of detected gene alterations tended to be large. Two patients with small cell carcinoma transformation had RB1 mutations and MYC amplification. Conclusions: Regardless of the test system, the detection of T790M could predict a good therapeutic effect of osimertinib, but there was no difference in response to osimertinib depending on EGFR T790M AF. Compared to single-gene assessment of EGFR, NGS of cfDNA may be useful for guiding treatment decisions for patients with TKI-resistant NSCLC. Clinical trial information: UMIN000025930.

scholarly journals Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients

2015 ◽  
Vol 10 (10) ◽  
pp. 1437-1443 ◽  
Author(s):  
Antonio Marchetti ◽  
John F. Palma ◽  
Lara Felicioni ◽  
Tommaso M. De Pas ◽  
Rita Chiari ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egfr Mutations ◽  
Early Prediction ◽  
Prediction Of Response ◽  
Nsclc Patients
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