Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Yang, Yang; Li, Shuo; Wang, Yujiao; Zhao, Yang; Li, Qiu

doi:10.1038/s41392-022-01168-8

Cited by 91 publications

(67 citation statements)

References 482 publications

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“…MTD of palbociclib was set at 75 mg/m 2 (as monotherapy) for 21 days, followed by 7 days without medication. Neutropenia and thrombocytopenia were common AEs; no objective responses were observed among 35 enrolled patients [ 938 ].…”

Section: Kinase Inhibitors In Clinical Trialsmentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

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Section: Kinase Inhibitors In Clinical Trialsmentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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“…A molecular mechanism can lead to a dysregulated signal cascade mechanism, mainly resulting in malignancy and other pathologies. TKIs compete with ATP for the ATP binding site of PTK and completely block PTK-mediated signalling pathways, inhibiting cancer cell proliferation ( Alexander et al, 2017 ; Yang et al, 2022 ). TKIs are more efficient than conventional treatments, dimers activate the HER2 extracellular domain, causing TK residues in the cytoplasmic domain to be phosphorylated ( Alexander et al, 2017 ; Alexander et al, 2017 ).…”

Section: Receptor Tyrosine Kinasesmentioning

confidence: 99%

“…Current treatment option has shown limited efficacy in patient with HER2+ BC and causes adverse rection and rapid drug resistance, so the urgent requirement is targeted treatment for effective clinical outcome ( Yang et al, 2022 ). Nanoscience and technology could have important role in early detection, targeted drug delivery to reduce disease burden.…”

Section: Nanotechnology To Treat Her2-positive Bcmentioning

confidence: 99%

Clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer

2022

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Breast cancer (BC) is caused by epigenetic modifications and genetic heterogeneity and exhibits various histological feature. HER2+ (Human epidermal growth factor receptor 2) is a more aggressive type of breast cancer, diagnosis and prognosis are difficult for HER2+ BC. Anti-HER2+ inhibitors have been effectively used for patient treatment. High mortality rate is reported in HER2+ BC, due to availability of limited therapeutic options. Despite advances in systemic medications to treat metastatic breast cancer (MBC), HER2-positive MBC is still challenging for patients and treating clinicians. The clinical characteristics of the disease have changed after treatment with HER2-targeted therapy. Various types of Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with HER2+ BC including afatinib, lapatinib, neratinib, tucatinib, and pyrotinib, have been developed as HER2-targeted therapies. The antibody-drug conjugates adotrastuzumab, emtansine, famtrastuzumab, and deruxtecan, as well as the anti-HER2 monoclonal antibody pertuzumab are used in both early-stage and metastatic situations, either alone or in conjunction with chemotherapy and other HER2-targeting therapies. The emergence of drug resistance in anti-HER2 therapies has been observed. To overcome drug resistance and limited efficacy in current treatment options, nano formulations can be used in patients with HER2+ BC treatment. Anti-HER2 ligands can be used in various nano formulations to target HER2 receptors. Here we will discuss, targeted TKIs in patients with HER2+ BC, clinical studies of HER2+ targeted TKIs, mechanisms of resistance to HER2-directed therapies with new implications of TKIs in HER2+ MBC (metastatic breast cancer) and anti-HER2 ligand in various nano formulations to target HER2 receptors.

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“…Members of the receptor tyrosine kinases (RTK) family including cytokine receptors EpoR (via JAK2 V617F ) and members of the epidermal growth factor receptor (ErbB; HER) family represent the most common oncogenic drivers of malign carcinomas (Gschwind et al, 2004; Lemmon and Schlessinger, 2010; Schmidt-Arras and Böhmer, 2020). However, despite their immense clinical relevance, conventional drug discovery approaches have shown limited efficacy and problems of resistance (Chong and Jänne, 2013; Yang et al, 2022). These limitations are mainly due to the nature of primary and emerging secondary escape mutations in the receptor (EGFR T790M ) and acquired resistance as well as pathway mutations e.g.…”

Section: Mainmentioning

confidence: 99%

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

Siepe

Picton

Garcia

2022

Preprint

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In recent years, targeted protein degradation (TPD) of plasma membrane proteins by hijacking the ubiquitin proteasome system (UPS) or the lysosomal pathway have emerged as novel therapeutic avenues in drug development to address and inhibit canonically difficult targets. While TPD strategies have been successful to target cell surface receptors, these approaches are limited by the availability of suitable binders to generate heterobifunctional molecules. Here, we present the development of a nanobody (VHH) based degradation toolbox termed REULR (Receptor Elimination by E3 Ubiquitin Ligase Recruitment). We generated human and mouse cross-reactive nanobodies against 5 transmembrane PA-TM-RING type E3 Ubiquitin Ligases (RNF218, RNF130, RNF167, RNF43, ZNRF3) covering a broad range and selectivity of tissue expression with which we characterized expression in human and mouse cell lines and immune cells (PBMCs). We demonstrate that heterobifunctional REULR molecules can enforce transmembrane E3 ligase interaction with a variety of disease relevant target receptors (EGFR, EPOR, PD-1) by induced proximity resulting in effective membrane clearance of the target receptor at varying levels. In addition, we designed E3 Ligase self-degrading molecules, "fratricide" REULRs (RNF128, RNF130, RENF167, RNF43, ZNRF3), that allow downregulation of one or several E3 Ligases from the cell surface and consequently modulate receptor signaling strength. REULR molecules represent a VHH-based, modular and versatile "mix and match" targeting strategy for facile modulation of cell surface proteins by induced proximity to transmembrane PA-TM-RING E3 ligases.

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Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Cited by 91 publications

References 482 publications

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

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