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Cancer Research Oct 2022Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the...
UNLABELLED
Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR-STAT3-ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft-dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR-STAT3-ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease.
SIGNIFICANCE
HCC cells acquire resistance to lenvatinib by activating the EGFR-STAT3-ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.
Topics: ATP Binding Cassette Transporter, Subfamily B; Carcinoma, Hepatocellular; Cell Line, Tumor; Cholesterol; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Liver Neoplasms; Phenylurea Compounds; Quinolines; STAT3 Transcription Factor; Tyrosine
PubMed: 36066408
DOI: 10.1158/0008-5472.CAN-21-4140 -
International Journal of Cancer Jun 2017Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung... (Comparative Study)
Comparative Study Meta-Analysis Review
Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung cancer (NSCLC) with proven efficacy. We undertook a systematic review and meta-analysis to synthesize existing studies with direct comparisons of EGFR TKIs in NSCLC in terms of both efficacy and safety. Eight randomized trials and 82 cohort studies with a total of 17,621 patients were included for analysis. Gefitinib and erlotinib demonstrated comparable effects on progression-free survival (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.95 to 1.04), overall survival (HR, 0.99; 95% CI, 0.93 to 1.06), overall response rate (risk ratio [RR], 1.05; 95% CI, 1.00 to 1.11), and disease control rate (RR, 0.98; 95% CI, 0.96 to 1.01), which did not vary considerably with EGFR mutation status, ethnicity, line of treatment, and baseline brain metastasis status. Gefitinib was associated with more grade 3/4 liver dysfunction, but tended to cause lower rates of dose reduction, treatment discontinuation, total grade 3/4 adverse events (RR, 0.78; 95% CI 0.65 to 0.94), and a number of specific adverse events such as rash and diarrhea. No solid evidence was found that afatinib had greater efficacy than gefitinib or erlotinib in first-line treatment of EGFR-mutant NSCLC. However, afatinib was more effective than erlotinib as second-line treatment of patients with advanced squamous cell carcinoma. The grade 3/4 adverse events rate of afatinib was comparable to that of erlotinib but higher than that of gefitinib.
Topics: Afatinib; Carcinoma, Non-Small-Cell Lung; Diarrhea; Disease-Free Survival; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Gefitinib; Humans; Lung Neoplasms; Mutation; Outcome Assessment, Health Care; Proportional Hazards Models; Protein Kinase Inhibitors; Quinazolines; Randomized Controlled Trials as Topic
PubMed: 28295308
DOI: 10.1002/ijc.30691 -
Cancer Cell Sep 2021Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may delay therapeutic resistance in advanced non-small... (Comparative Study)
Comparative Study
Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may delay therapeutic resistance in advanced non-small cell lung cancer (NSCLC). This phase 3 study investigated the efficacy and safety of an erlotinib plus bevacizumab regimen in untreated patients with advanced NSCLC. In total, 311 patients received bevacizumab plus erlotinib (n = 157) or erlotinib only (n = 154). Progression-free survival (PFS) was 17.9 months (95% confidence interval [CI], 15.2-19.9) for bevacizumab plus erlotinib and 11.2 months (95% CI, 9.7-13.8) for erlotinib only (hazard ratio [HR] = 0.55; 95% CI, 0.41-0.73; p < 0.001). A brain metastases subgroup treated with bevacizumab plus erlotinib also showed improved PFS (HR = 0.48; 95% CI, 0.27-0.84; p = 0.008). Grade ≥3 treatment-related adverse events occurred in 86 (54.8%) and 40 (26.1%) patients, respectively. Bevacizumab plus erlotinib significantly improved PFS in patients with untreated metastatic EGFR-mutated NSCLC, including those with brain metastases at baseline.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Random Allocation; Survival Analysis; Treatment Outcome
PubMed: 34388377
DOI: 10.1016/j.ccell.2021.07.005 -
Journal of Clinical Oncology : Official... Feb 2023Overexpression of c-Met protein and epidermal growth factor receptor () mutations can co-occur in non-small-cell lung cancer (NSCLC), providing strong rationale for dual...
PURPOSE
Overexpression of c-Met protein and epidermal growth factor receptor () mutations can co-occur in non-small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met-positive (+) NSCLC.
PATIENTS AND METHODS
This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an -activating mutation (-M) and progression on a prior EGFR TKI. End points included safety, pharmacokinetics, objective response rate (ORR), and progression-free survival (PFS). The efficacy-evaluable population consisted of c-Met+ patients (confirmed histology [H]-score ≥ 150) who had at least one postbaseline scan; c-Met+ patients with H-scores ≥ 225 were classified as c-Met high.
RESULTS
As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 to not reached). ORR for -M patients (n = 28) was 32.1%. Of M patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was 6.8 months for non-T790M+ and for those whose T790M status was unknown, versus 3.7 months for T790M+.
CONCLUSION
Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients with -M+, c-Met+ NSCLC.
Topics: Adult; Humans; Adolescent; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Lung Neoplasms; Mutation; ErbB Receptors; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36288547
DOI: 10.1200/JCO.22.00739 -
Pharmacological Research May 2023Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase...
Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. β-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that β-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that β-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Ferroptosis; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; RNA, Long Noncoding; Sesquiterpenes
PubMed: 36948327
DOI: 10.1016/j.phrs.2023.106739 -
Indian Journal of Ophthalmology Apr 2023
Topics: Humans; Erlotinib Hydrochloride; Dry Eye Syndromes; Lung Neoplasms
PubMed: 37026321
DOI: 10.4103/IJO.IJO_2582_22 -
British Journal of Cancer Nov 2020A trial update confirms improved survival for prophylactic elective nodal irradiation and addition of erlotinib to definitive chemoradiotherapy in oesophageal squamous...
A trial update confirms improved survival for prophylactic elective nodal irradiation and addition of erlotinib to definitive chemoradiotherapy in oesophageal squamous cell carcinoma (ESCC). High tumour EGFR protein expression shows promise to identify those who will benefit from erlotinib. This represents therapeutic progress, and has wider relevance for precision medicine strategies in ESCC.
Topics: Carcinoma, Squamous Cell; Chemoradiotherapy; Erlotinib Hydrochloride; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Head and Neck Neoplasms; Humans; Precision Medicine
PubMed: 32958821
DOI: 10.1038/s41416-020-01057-3 -
Advanced Science (Weinheim,... Dec 2023Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of...
Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU-1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU-1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c-MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p-PLCG1 and p-Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient-derived xenograft (PDX) models, AU-1 monotherapy exhibited remarkable tumor-inhibiting activity and is synergistic anti-tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c-MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC.
Topics: Humans; Erlotinib Hydrochloride; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Stomach Neoplasms; Drug Resistance, Neoplasm; Cell Line, Tumor; Phospholipase C gamma
PubMed: 37863665
DOI: 10.1002/advs.202303091 -
PloS One 2023Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study...
BACKGROUND
Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in the first-line treatment of patients with aHCC.
METHODS
A three-state Markov model was established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes in this study were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER).
RESULTS
The total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33,814 and 0.45, $49,120 and 0.83, $63,064 and 0.81, $74,814 and 0.82, $81,995 and 0.82, $74083 and 0.85, and $104,188 and 0.84, respectively. The drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib ($68,869 per QALY). For oral multikinase inhibitors, the ICER of lenvatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534,347, $1768,971, and $1963,064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs.
CONCLUSION
For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab.
Topics: Humans; Carcinoma, Hepatocellular; Sorafenib; Bevacizumab; Sunitinib; Cost-Effectiveness Analysis; Erlotinib Hydrochloride; Liver Neoplasms; Cost-Benefit Analysis; Quality-Adjusted Life Years
PubMed: 37053300
DOI: 10.1371/journal.pone.0279786 -
Antiviral Research Jul 2018There is an urgent need for strategies to combat dengue virus (DENV) infection; a major global threat. We reported that the cellular kinases AAK1 and GAK regulate...
There is an urgent need for strategies to combat dengue virus (DENV) infection; a major global threat. We reported that the cellular kinases AAK1 and GAK regulate intracellular trafficking of multiple viruses and that sunitinib and erlotinib, approved anticancer drugs with potent activity against these kinases, protect DENV-infected mice from mortality. Nevertheless, further characterization of the therapeutic potential and underlying mechanism of this approach is required prior to clinical evaluation. Here, we demonstrate that sunitinib/erlotinib combination achieves sustained suppression of systemic infection at approved dose in DENV-infected IFN-α/β and IFN-γ receptor-deficient mice. Nevertheless, treatment with these blood-brain barrier impermeable drugs delays, yet does not prevent, late-onset paralysis; a common manifestation in this immunodeficient mouse model but not in humans. Sunitinib and erlotinib treatment also demonstrates efficacy in human primary monocyte-derived dendritic cells. Additionally, DENV infection induces expression of AAK1 transcripts, but not GAK, via single-cell transcriptomics, and these kinases are important molecular targets underlying the anti-DENV effect of sunitinib and erlotinib. Lastly, sunitinib/erlotinib combination alters inflammatory cytokine responses in DENV-infected mice. These findings support feasibility of repurposing sunitinib/erlotinib combination as a host-targeted antiviral approach and contribute to understanding its mechanism of antiviral action.
Topics: Animals; Antiviral Agents; Cells, Cultured; Dendritic Cells; Dengue; Dengue Virus; Drug Repositioning; Erlotinib Hydrochloride; Feasibility Studies; Female; Gene Expression Profiling; Humans; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Protein Serine-Threonine Kinases; Single-Cell Analysis; Sunitinib; Virus Replication
PubMed: 29753658
DOI: 10.1016/j.antiviral.2018.05.001