scholarly journals Case Report: Sequential Combination Targeted Therapy With Type I and II MET Inhibitors in a Metastatic EGFR-Mutated, MET-Amplified NSCLC Patient With Acquired MET Y1230H Mutation

2021 ◽  
Vol 11 ◽  
Author(s):  
Boning Cai ◽  
Xiaomo Li ◽  
Xiang Huang ◽  
Tonghui Ma ◽  
Baolin Qu ◽  
...  
Keyword(s):  
Partial Response ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Nsclc Patient ◽  
Acquired Resistance ◽  
Molecular Testing ◽  
Type I ◽  
Formidable Challenge ◽  
Dual Blockade ◽  
Nsclc Patients

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for advanced non-small-cell lung cancer (NSCLC) patients. However, most patients will eventually develop resistance. For EGFR-TKI resistance mediated by MET amplification, the combination of EGFR and MET TKIs has shown promising results in early clinical trials. However, acquired resistance to MET inhibitors forms a formidable challenge to this dual blockade approach. Here, we presented an NSCLC patient with EGFR exon 19 deletion (ex19del) who was resistant to first-line erlotinib treatment but responded to chemotherapy. Given the finding of MET overexpression/amplification after disease progression, the patient received gefitinib plus crizotinib with a partial response. Her disease progressed again, and molecular testing revealed a novel MET Y1230H mutation and a PD-L1 TPS score of 75%. She received a salvage regime consisting of gefitinib, cabozantinib, and pembrolizumab with a partial response. Since we now know that EGFR ex19del NSCLC patients generally do not respond to PD-1 blockade therapy, this response is more likely the contribution from gefitinib plus cabozantinib. Therefore, sequential use of type I and II MET inhibitors in EGFR/MET dual blockade may be an effective therapeutic option for EGFR-mutant, MET-amplified NSCLC.

scholarly journals Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

ESMO Open ◽  
2019 ◽  
Vol 4 (5) ◽  
pp. e000561 ◽  
Author(s):  
Anastasia Kougioumtzi ◽  
Panagiotis Ntellas ◽  
Eirini Papadopoulou ◽  
George Nasioulas ◽  
Eleftherios Kampletsas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Molecular Testing ◽  
Liquid Biopsies ◽  
Disease Biology ◽  
Remarkable Progress

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable.Method: Here, we present the case of a patient with NSCLC treated with TKIs, in which molecular profiling of the tumour was performed with different methods of tissue and plasma testing at each disease progression. A review of the literature was further conducted to offer insights into the resistance mechanisms of ALK-rearranged NSCLC.Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional ALK mutations were later detected in the tissue and plasma and are likely to have caused resistance to the administered TKIs. Continued research into the mechanisms of acquired resistance is required in order to increase the benefit of the patients treated with targeted ALK TKIs.

Acquired resistance to MET inhibition in MET driven NSCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9030-9030
Author(s):  
Richard Riedel ◽  
Carina Heydt ◽  
Andreas H. Scheel ◽  
Hannah Lea Tumbrink ◽  
Johannes Brägelmann ◽  
...  
Keyword(s):  
Partial Response ◽  
Tyrosine Kinase ◽  
Single Agent ◽  
Acquired Resistance ◽  
Kinase Domain ◽  
Type I ◽  
Type Ii ◽  
Low Level ◽  
Met Amplification ◽  
High Level

9030 Background: MET mutations ( MET∆ex14), amplifications or translocations can activate oncogenic signaling in lung cancer and are sensitive to MET inhibition. Acquired resistance to therapy with MET tyrosine kinase inhibitors (TKI) occurs inevitably. Methods: Between 2015 and 2018, eighteen patients with MET-driven NSCLC were treated with capmatinib or crizotinib as single agent at our site. Rebiopsy samples from five patients were analyzed by NGS and fluoreszenz-in-situ hybridization (FISH) at time of progression. Results: Of the five patients with rebiopsy samples at time of progression, two had initially a MET amplification (one patient with low-level and one patient with high-level amplification), two patients had a MET∆ex14 and one patient had a KIF5B-MET fusion. Patient 1 (low-level MET amplification) showed a partial response to crizotinib. The rebiopsy revealed an acquired KRAS mutation as a potential mechanism of resistance. Patient 2 (high-level MET amplification) showed stable disease as best response to capmatinib and patient 3 (MET∆ex14) showed a partial response to capmatinib. Both patients developed acquired HER2 amplifications. Patient 4 ( MET∆ex14) showed initially a partial response to crizotinib. The rebiopsy sample revealed an acquired MET kinase domain mutation (p.D1246N). As preclinical findings suggested that D1246N confers resistance to type I MET inhibitors but remains sensitive to type II inhibitors, cabozantinib was started. A CT six weeks after therapy initiation showed progressive disease. Patient 5 ( KIF5B-MET) had a partial response to crizotinib. An acquired MET p.Y1248H mutation was found at time of progression. Therapy was changed to cabozantinib. A new CT scan is pending. Conclusions: Resistance to MET inhibition is heterogeneous with on- and off-target-mechanisms occurring. We found HER2 amplification as a potential new bypass mechanism. The MET mutation D1246N conferred resistance to type I and type II inhibitors. We describe the first case of an acquired mutation of the MET tyrosine kinase domain in a patient with an oncogenic MET fusion. Further investigations are needed to collect comprehensive data to understand resistance mechanisms in MET inhibition and to develop novel therapeutic strategies.

The targetable mutation landscape of Chinese patients with non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13018-e13018
Author(s):  
Jun Li ◽  
Cuiyun Zhang ◽  
Jiuzhou Zhao ◽  
Zhizhong Wang ◽  
Bing Wei ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Chinese Patients ◽  
Molecular Testing ◽  
Small Cell Lung ◽  
Essential Information ◽  
Nsclc Patients

e13018 Background: In recent years, the prognosis of non-small cell lung cancer (NSCLC) patients has been substantially improved by targeted therapies against specific molecular aberrations, i.e. tyrosine kinase inhibitors (TKIs) for Epidermal Growth Factor Receptor ( EGFR) etc. Several genes have been suggested by NCCN guideline (v7.2017) to test for NSCLC patients, including EGFR, ALK, ROS1, BRAF, MET, RET, HER2 and KRAS. The aim of this study is to profile the landscape of actionable mutations in Chinese NSCLC patients. Methods: From 2015 to 2017 621 treatment naïve NSCLC patients enrolled in the affiliated cancer hospital of Zhengzhou University were included in this analysis. DNA was extracted from the FFPE biopsies of these patients and processed for target capture sequencing covering the exons and flanking splicing regions of the 8 genes suggested by NCCN guideline, as well as introns of ROS, ALK and RET. Results: In total, 593 out of the 621 NSCLC patients harbor one or more mutations in these 8 genes, accounting for 95.5% of all the cases. EGFR, ALK and HER2 are the top 3 mutants, with a frequency of 52%, 32% and 26% respectively. Genetic aberrations in BRAF, MET, ROS1, KRAS and RET occur in 22%, 18%, 16% and 14% of the patients. The most common variation is missense; T > G, C > T and C > A changes are more often observed than T > C, T > A and C > G; the median number of variants per sample is 2, ranging from 1 to 13. There are 418 mutations detected on EGFR, of which 206 (49.28%) are clinically relevant. EGFR L858R, Exon19 deletion, Exon20 insertion, G719, A750P were observed in 123 (29.43%), 43 (10.29%), 8 (1.91%), 6 (1.44%) and 6 (1.44%) cases respectively. Gene fusions were identified in 78 cases, and the EML4- ALK is the most common one occurred in 54 patients, other fusion genes include KIF5B- ALK (11) ， CCDC6- RET (4), CD74- ROS1 (4), EZR- ROS1 (2), ERC1- RET (1), , SDC4- ROS1 (1) and TCOF1- ROS1 (1). Conclusions: Target sequencing of the 8 genes suggested by NCCN guideline for NSCLC patients reveals essential information for designing personalized therapeutic regimen. Chinese patients, maybe other Asian countries also, may benefit more from this molecular testing, because of the high occurrence of actionable mutations.

scholarly journals MET Gene Dysregulation as a Promising Therapeutic Target in Lung Cancer—A Review

2021 ◽  
Vol 11 (12) ◽  
pp. 1370
Author(s):  
Paulina Terlecka ◽  
Paweł Krawczyk ◽  
Anna Grenda ◽  
Janusz Milanowski
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Molecular Abnormalities ◽  
Promising Therapeutic Target ◽  
Tumorigenic Activity ◽  
Nsclc Patients

Several molecular abnormalities in the MET gene have been identified, including overexpression, amplification, point mutations, and “skipping mutation” in exon 14. Even though deregulated MET signaling occurs rarely in non-small cell lung cancer (NSCLC), it possesses tumorigenic activity. Since the discovery of the significant role played by MET dysregulations in resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), many clinical trials have been focused on mechanisms underlying this acquired resistance. Therefore, new therapeutic strategies are being considered in the personalized therapy of NSCLC patients carrying MET abnormalities. First, MET kinase inhibitors (tepotinib and capmatinib) have been shown to be effective in the first and subsequent lines of treatment in NSCLC patients with “skipping mutations” in exon 14 of MET gene. In this article, the authors show the role of MET signaling pathway alterations and describe the results of clinical trials with MET inhibitors in NSCLC patients.

Comparison of circulating tumor DNA (ctDNA) sequencing and tumor-based genotyping for the detection of EGFR mutations in non-small cell lung cancer (NSCLC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20586-e20586
Author(s):  
Allen Li ◽  
Sanja Dacic ◽  
Timothy Francis Burns ◽  
Mark A. Socinski ◽  
Shira Abberbock ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Kinase Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
High Specificity ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
High Concordance ◽  
Egfr Tkis

e20586 Background: Therapy for NSCLC is based on detection of actionable oncogenic drivers. Conventionally, targetable mutations are detected by tissue biopsy, which may be insufficient for molecular testing. Repeat biopsy is often required at the time of disease progression. Guardant360™ (G360) utilizes digital next-generation sequencing (NGS) to analyze ctDNA in plasma. Limited data exists on clinical outcomes of 3rd generation EGFR tyrosine kinase inhibitors (TKIs) against T790M-mediated resistance detected by digital NGS in ctDNA. We hypothesize that G360 has high concordance in detecting actionable oncogenic drivers and similar clinical outcomes compared with tumor-based genotyping. Methods: G360 (Guardant Health, Inc.) was performed in 20 advanced NSCLC patients (pts) with matched tumor-based genotyping by either Sanger sequencing (N = 10) or Ion Torrent ApliSeq v.2 NGS (N = 10; Life Technologies, Fisher Scientific). Matched genotypes were done at diagnosis (N = 12) or at time of acquired resistance (N = 8). Sensitivity, specificity, and response to EGFR TKIs (RECIST V1.1) were determined. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method. Objective response rates (ORR) were calculated by MedCalc(r) software. Results: Compared with tumor-based testing, G360 has high concordance for EGFR exon 19 deletion, T790M and L858R (90%, 85% and 100%, respectively) and high specificity (100%, 93.3%, and 100%, respectively). OS of pts with T790M or L858R were similar between those detected by G360 and by tumor-based testing (p > 0.99). Pts who received 3rd generation EGFR TKIs (4 osimertinib, 1 PF-06747775) after detected T790M in plasma (N = 4) had similar ORR (50% vs 25% with difference of 25%, 95% CI (-0.45 to 0.75)) and median PFS (7.5 vs 6.0 mos, p = 0.63) as those detected by tumor-based testing (N = 4). Conclusions: G360 showed high concordance for EGFR actionable mutations. Clinical outcomes of 3rd generation EGFR TKI treatment in T790M+ disease were similar between those detected by G360 and those detected by tumor testing. G360 represents a viable option for pts who are not candidates for solid tumor biopsies.

scholarly journals Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease

2020 ◽  
Vol 318 (5) ◽  
pp. F1067-F1073
Author(s):  
Shohei Mitsui ◽  
Yuji Oe ◽  
Akiyo Sekimoto ◽  
Emiko Sato ◽  
Yamato Hashizume ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Therapeutic Option ◽  
Collagen Type Iv ◽  
Type I ◽  
Glomerular Injury ◽  
Plasminogen Activator Inhibitor 1 ◽  
Diabetic Kidney ◽  
Dual Blockade ◽  
Akita Mice

Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Mice (4 mo old) were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg·kg−1·day−1), PAR2 antagonist (FSLLRY, 3 mg·kg−1·day−1), or E5555 + FSLLRY for 4 wk. The results showed that the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 + FSLLRY compared with the vehicle-treated group. Dual blockade of PAR1 and PAR2 by E5555 + FSLLRY additively ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and collagen type IV deposition. Marked reduction of inflammation- and fibrosis-related gene expression in the kidney was also observed. In vitro, PAR1 and PAR2 agonists additively increased mRNA expression of macrophage chemoattractant protein 1 or plasminogen activator inhibitor-1 in human endothelial cells. Changes induced by the PAR1 agonist were blocked by a NF-κB inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-κB inhibitors. These findings suggest that PAR1 and PAR2 additively contribute to DKD pathogenesis and that dual blockade of both could be a novel therapeutic option for treatment of patients with DKD.

scholarly journals Tumour tissue sampling for lung cancer management in the era of personalised therapy: what is good enough for molecular testing?

2014 ◽  
Vol 44 (4) ◽  
pp. 1011-1022 ◽  
Author(s):  
Lucia Kim ◽  
Ming Sound Tsao
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Tumour Progression ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Tumour Tissue ◽  
Molecular Testing ◽  
Anaplastic Lymphoma ◽  
Cancer Management ◽  
Nsclc Patients

In the era of personalised cancer therapy, the demand for molecular profiling of the patient’s tumour is steadily increasing. In advanced nonsmall cell lung cancer (NSCLC) patients, testing for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements has become an essential component of clinical practice to select patients who are most likely to benefit from EGFR and ALK tyrosine kinase inhibitors, respectively. Furthermore, obtaining tissue specimens from recurrent or metastatic tumours or from patients who develop resistance to initial effective therapies are essential for our understanding of the molecular basis of tumour progression and development of drug resistance. Therefore, the sampling of tumour tissue that is representative and is adequate in quantity and quality for pathological diagnosis and genomic profiling is crucial. In this review, we will discuss factors that should be considered in obtaining and processing biopsy specimens to enable routine molecular analysis in NSCLC patients.

Enhanced detection of EGFR mutations in plasma from non-small cell lung cancer (NSCLC) patients using Scorpion primers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7682-7682
Author(s):  
W. Holland ◽  
A. M. Davies ◽  
N. C. Farneth ◽  
O. Gautschi ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Genomic Dna ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Nsclc Patient ◽  
Detection Methods ◽  
Egfr Mutations ◽  
Wild Type ◽  
Allele Specific ◽  
Nsclc Patients ◽  
Tumor Dna

7682 Background: Activating epidermal growth factor receptor (EGFR) mutations identified in NSCLC patient tumors are often associated with rapid and profound response to EGFR tyrosine kinase inhibitors (TKIs). Conventional detection methods are cumbersome and may underestimate mutations frequencies due to limited sensitivity. We and others have shown that tumor-specific mutations such as KRAS can be detected in tumor DNA shed into patient plasma (Kimura, Ann N Y Acad Sci, 2004). Here we describe the performance of an allele- specific real-time PCR system utilizing Scorpion primers (kindly provided by DxS, UK) to detect EGFR mutations in plasma. Methods: DNA was extracted from archival tumor blocks, slides and plasma obtained from consenting patients. In order to determine the sensitivity of this technique both in terms of the ratio of mutant-to-wild-type genomic DNA as well as the minimum amount of DNA required for detection, a dilution experiment was conducted. Genomic DNA from cell lines containing either the exon 21 L858R point mutation or the exon 21 E746–750 deletion was diluted with wild-type genomic DNA at ratios ranging from 1:2 to 1:10,000. Clinical specimens including plasma and/or tissue from 35 advanced stage NSCLC patients treated with EGFR-TKIs were examined. Results: Mutant DNA was successfully detected when it comprised as little as 0.1% of the total sample or as low as 25 pg of mutant-positive genomic DNA in a pool of 2.5 μg of total DNA. EGFR mutations were identified by this approach in both plasma and tissue of 2 patients who were complete responders to EGFR-TKI therapy, only one of which was detectable by direct sequencing. For the 7 patients where only tissue was available, two were positive both with the Scorpion primers and direct sequencing while the rest were wild-type. Of 21 patients where only plasma was available, 6 mutations were detected using the Scorpion primers. Conclusions: Allele-specific Scorpion technology is 1) highly specific and sensitive for EGFR mutation analysis, 2) able to detect mutations that were not observable by direct sequencing in plasma and tissue, 3) capable of detecting mutations in shed tumor DNA in plasma of advanced NSCLC patients and 4) may be suitable for monitoring response or detecting recurrence. No significant financial relationships to disclose.

Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20576-e20576
Author(s):  
Ying Jin ◽  
Jianjun Zhang ◽  
Ming Chen ◽  
Yang Shao ◽  
Xun Shi ◽  
...  
Keyword(s):  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Targeted Next Generation Sequencing ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr T790m

e20576 Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.

scholarly journals PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs

Oncogene ◽  
2021 ◽  
Author(s):  
Chia-Hung Chen ◽  
Bo-Wei Wang ◽  
Yu-Chun Hsiao ◽  
Chun-Yi Wu ◽  
Fang-Ju Cheng ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

AbstractThe tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.

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