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International Journal of Molecular... Sep 2023The development of targeted therapies has revolutionized cancer treatment, offering improved efficacy with reduced side effects compared with traditional chemotherapy.... (Review)
Review
The development of targeted therapies has revolutionized cancer treatment, offering improved efficacy with reduced side effects compared with traditional chemotherapy. This review highlights the current landscape of targeted therapy in lung cancer, colorectal cancer, and prostate cancer, focusing on key molecular targets. Moreover, it aligns with US Food and Drug Administration (FDA)-approved drugs and drug candidates. In lung cancer, mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene rearrangements have emerged as significant targets. FDA-approved drugs like osimertinib and crizotinib specifically inhibit these aberrant pathways, providing remarkable benefits in patients with EGFR-mutated or ALK-positive lung cancer. Colorectal cancer treatment has been shaped by targeting the vascular endothelial growth factor (VEGF) and EGFR. Bevacizumab and cetuximab are prominent FDA-approved agents that hinder VEGF and EGFR signaling, significantly enhancing outcomes in metastatic colorectal cancer patients. In prostate cancer, androgen receptor (AR) targeting is pivotal. Drugs like enzalutamide, apalutamide, and darolutamide effectively inhibit AR signaling, demonstrating efficacy in castration-resistant prostate cancer. This review further highlights promising targets like mesenchymal-epithelial transition (MET), ROS1, BRAF, and poly(ADP-ribose) polymeras (PARP) in specific cancer subsets, along with ongoing clinical trials that continue to shape the future of targeted therapy.
Topics: United States; Male; Humans; Vascular Endothelial Growth Factor A; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Prostatic Neoplasms; Lung Neoplasms; ErbB Receptors; Colonic Neoplasms
PubMed: 37686423
DOI: 10.3390/ijms241713618 -
Molecular Cancer Therapeutics Sep 2023HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric,...
HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the first successful HER3-targeting antibody-drug conjugate (ADC) with clinical efficacy in non-small cell lung cancer. However, over 60% of patients are nonresponsive to U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels. U3-1402 is also ineffective in more challenging tumor types such as colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562 and a modified self-immolative PABC spacer (T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate affinity for minimizing potential toxicity and improving tumor penetration purposes. Both alone or in combination therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/organoid models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 with therapeutic antibodies, inhibitors of CHEK1, KRAS, and tyrosine kinase inhibitor showed higher synergistic efficacy than Patritumab-GGFG-DXd. Pharmacokinetic and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402-insensitive tumors.
Topics: Male; Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immunoconjugates; Receptor, ErbB-3; ErbB Receptors; Cell Line, Tumor
PubMed: 37302522
DOI: 10.1158/1535-7163.MCT-23-0198 -
Proceedings of the National Academy of... Aug 2023Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor () copy...
Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor () copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that is always coamplified with and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8 T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of -amplified GBMs.
Topics: Animals; Mice; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; ErbB Receptors; Glioblastoma; SEC Translocation Channels
PubMed: 37523556
DOI: 10.1073/pnas.2303400120 -
EMBO Molecular Medicine Jun 2023Particulate matter 2.5 (PM2.5) is a risk factor for lung cancer. In this study, we investigated the molecular mechanisms of PM2.5 exposure on lung cancer progression. We...
Particulate matter 2.5 (PM2.5) is a risk factor for lung cancer. In this study, we investigated the molecular mechanisms of PM2.5 exposure on lung cancer progression. We found that short-term exposure to PM2.5 for 24 h activated the EGFR pathway in lung cancer cells (EGFR wild-type and mutant), while long-term exposure of lung cancer cells to PM2.5 for 90 days persistently promoted EGFR activation, cell proliferation, anchorage-independent growth, and tumor growth in a xenograft mouse model in EGFR-driven H1975 cancer cells. We showed that PM2.5 activated AhR to translocate into the nucleus and promoted EGFR activation. AhR further interacted with the promoter of TMPRSS2, thereby upregulating TMPRSS2 and IL18 expression to promote cancer progression. Depletion of TMPRSS2 in lung cancer cells suppressed anchorage-independent growth and xenograft tumor growth in mice. The expression levels of TMPRSS2 were found to correlate with nuclear AhR expression and with cancer stage in lung cancer patient tissue. Long-term exposure to PM2.5 could promote tumor progression in lung cancer through activation of EGFR and AhR to enhance the TMPRSS2-IL18 pathway.
Topics: Humans; Mice; Animals; Particulate Matter; Interleukin-18; Signal Transduction; Lung Neoplasms; ErbB Receptors; Serine Endopeptidases
PubMed: 36975376
DOI: 10.15252/emmm.202217014 -
Nature Communications Aug 2023Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete...
Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Genomics; Brain Neoplasms; ErbB Receptors
PubMed: 37591896
DOI: 10.1038/s41467-023-40793-x -
Japanese Journal of Clinical Oncology Jun 2023Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA... (Review)
Review
Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA study. However, resistance inevitably hinders patient prognosis, increasing the need for new therapeutic strategies beyond osimertinib. Frontline osimertinib-based combination strategies (platinum-based chemotherapy and angiogenesis inhibitors) are currently being tested primarily to prevent initial resistance. In the later-line setting after osimertinib, many next-line therapeutic candidates have been actively examined in clinical trials. Notably, several drugs with novel mechanisms of action, such as antibody-drug conjugates and EGFR -MET bispecific antibodies, have shown promising efficacy despite the resistance mechanisms and are close to clinical application. In addition, genotype-based target strategies have been investigated for a better understanding of osimertinib resistance mechanisms based on molecular profiling tests at relapse. The C797S mutation and MET gene alterations are commonly identified following osimertinib resistance, for which targeting strategies are actively tested. This review describes current pharmacotherapeutic strategies for EGFR-mutated non-small cell lung cancer based on the results of clinical trials and the latest published data, broadly grouped into two sections: 1) EGFR TKIs-based combination therapy in the front-line setting and 2) novel therapeutic strategies after osimertinib resistance.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Protein Kinase Inhibitors; Neoplasm Recurrence, Local; Mutation; Drug Resistance, Neoplasm
PubMed: 37279591
DOI: 10.1093/jjco/hyad052 -
Cell Reports Jul 2023Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that...
Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCAs) and associated with poor ESCA prognosis. In addition, using ESCA cell lines and mouse models, we confirm the critical functions of NAT10 in promoting ESCA tumorigenesis and progression in vitro and in vivo. Mechanistically, NAT10 depletion reduces the abundance of ac4C-modified tRNAs and decreases the translation efficiencies of mRNAs enriched for ac4C-modified tRNA-decoded codons. We further identify EGFR as a key downstream target that facilitates NAT10's oncogenic functions. In terms of clinical significance, we demonstrate that NAT10 depletion and gefitinib treatment synergistically inhibit ESCA progression in vitro and in vivo. Our data indicate the mechanisms underlying ESCA progression at the layer of mRNA translation control and provide molecular insights for the development of effective cancer therapeutic strategies.
Topics: Animals; Mice; ErbB Receptors; Gefitinib; Neoplasms; Protein Biosynthesis; RNA, Transfer; Humans; Cell Line, Tumor; N-Terminal Acetyltransferases; Drug Resistance, Neoplasm
PubMed: 37463108
DOI: 10.1016/j.celrep.2023.112810 -
Nature Communications Jul 2023Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective...
Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
Topics: Humans; Glioblastoma; Temozolomide; Lysine; Methylation; TNF Receptor-Associated Factor 6; NFATC Transcription Factors; ErbB Receptors; Transcription Factors
PubMed: 37429858
DOI: 10.1038/s41467-023-39845-z -
Tumour Biology : the Journal of the... 2024Circulating tumor DNA (ctDNA), i.e., DNA shed from tumor cells into the bloodstream, is emerging as one of the most useful plasma biomarkers in patients with multiple... (Review)
Review
Circulating tumor DNA (ctDNA), i.e., DNA shed from tumor cells into the bloodstream, is emerging as one of the most useful plasma biomarkers in patients with multiple types of cancer, including patients with non-small cell lung cancer (NSCLC). Indeed, NSCLC was the first malignancy in which measurement of ctDNA was approved for clinical use, i.e., mutational testing of EGFR for predicting response to EGFR tyrosine kinase inhibitors in patients with advanced disease. Although historically the gold standard method for EGFR mutational analysis required tumor tissue, the use of ctDNA is more convenient and safer for patients, results in a faster turn-around-time for return of results, provides a more complete representation of genetic alteration in heterogeneous tumors and is less costly to perform. Emerging uses of ctDNA in patients with lung or suspected lung cancer include screening for early disease, surveillance following initial treatment and monitoring response to therapy in metastatic disease. For evaluating therapy response, ctDNA appears to be especially useful in patients receiving targeted therapies against driver oncogenes or immunotherapy. Further work should not only validate these emerging findings but also aim to optimize and standardize ctDNA assays.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; ErbB Receptors; Mutation; Biomarkers, Tumor
PubMed: 37270828
DOI: 10.3233/TUB-220044 -
Cancer Communications (London, England) Dec 2023Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In...
BACKGROUND
Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR-vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.
METHODS
Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis. A metabolism-associated RTK-fatty acid-gene signature was constructed and verified. MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo.
RESULTS
GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3 (ACSS3), acyl-CoA synthetase long-chain family member 3 (ACSL3), and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF-κB-dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.
CONCLUSIONS
Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.
Topics: Animals; Cell Line, Tumor; Energy Metabolism; ErbB Receptors; Fatty Acids; Glioblastoma; Ligases; Mevalonic Acid; Proto-Oncogene Proteins c-akt; Temozolomide
PubMed: 37920878
DOI: 10.1002/cac2.12502