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Molecular Cancer Aug 2023The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle... (Review)
Review
The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
Topics: Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Neoplasms
PubMed: 37596643
DOI: 10.1186/s12943-023-01827-6 -
Journal of Advanced Research Sep 2023Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation....
INTRODUCTION
Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined.
OBJECTIVES
We aimed to elucidate the potential roles of Metrnl in DCM.
METHODS
Gain- andloss-of-function experimentswere utilized to determine the roles of Metrnl in the pathological processes of DCM.
RESULTS
We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation.
CONCLUSION
Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.
Topics: Animals; Mice; Rats; AMP-Activated Protein Kinases; Autophagy; Autophagy-Related Protein-1 Homolog; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Myocytes, Cardiac; Nucleotidyltransferases
PubMed: 36334887
DOI: 10.1016/j.jare.2022.10.014 -
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 -
Science Advances Sep 2023EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling,...
EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. We previously found that stretch promotes mitosis via the stretch-activated ion channel Piezo1 and ERK signaling. Here, we show that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. While both EGF- and Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis and ERK activation, EGF relies on canonical tyrosine autophosphorylation, whereas Piezo1 involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with Piezo1 agonist promoted cell cycle re-entry via nuclear ERK, AP-1 (FOS and JUN), and YAP accumulation, typical of regenerative and malignant signaling. Our results suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling, suggesting an alternative therapeutic approach.
Topics: Epidermal Growth Factor; Signal Transduction; src-Family Kinases; Endocytosis; Mitosis; ErbB Receptors
PubMed: 37756411
DOI: 10.1126/sciadv.adi1328 -
Pharmacological Research Feb 2024Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st... (Review)
Review
Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 80 FDA-approved therapeutic agents that target about two dozen different protein kinases and seven of these drugs were approved in 2023. Of the approved drugs, thirteen target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), twenty block nonreceptor protein-tyrosine kinases, and 43 inhibit receptor protein-tyrosine kinases. The data indicate that 69 of these drugs are prescribed for the treatment of neoplasms. Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 80 approved drugs, nearly two dozen are used in the treatment of multiple diseases. The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.
Topics: Humans; Adult; Protein Kinase Inhibitors; Alopecia Areata; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Protein Serine-Threonine Kinases; Protein Kinases; Neoplasms
PubMed: 38216005
DOI: 10.1016/j.phrs.2024.107059 -
Signal Transduction and Targeted Therapy Dec 2023Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular... (Review)
Review
Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.
Topics: Humans; Mitogen-Activated Protein Kinase Kinases; Extracellular Signal-Regulated MAP Kinases; raf Kinases; Melanoma; Lung Neoplasms
PubMed: 38105263
DOI: 10.1038/s41392-023-01705-z -
Cancer Research Dec 2023Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve...
The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance.
UNLABELLED
Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER-co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.
SIGNIFICANCE
Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
Topics: Humans; Female; Breast Neoplasms; Receptors, Estrogen; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Estrogen Antagonists; Protein Kinase Inhibitors; Cyclin-Dependent Kinase 4; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37725704
DOI: 10.1158/0008-5472.CAN-23-0694 -
Cancer Gene Therapy Sep 2023Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the... (Review)
Review
Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the advances in primary and adjuvant therapies, patients still develop distant metastases and require novel therapies. Mitogen‑activated protein kinase (MAPK) cascades are crucial signaling pathways that regulate many cellular processes, including proliferation, differentiation, apoptosis, stress responses and cancer development. p38 Mitogen Activated Protein Kinases (p38 MAPKs) includes four isoforms: p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). p38 MAPK was first identified as a stress response protein kinase that phosphorylates different transcriptional factors. Dysregulation of p38 pathways, in particular p38γ, are associated with cancer development, metastasis, autophagy and tumor microenvironment. In this article, we provide an overview of p38 and p38γ with respect to gastrointestinal cancers. Furthermore, targeting p38γ is also discussed as a potential therapy for gastrointestinal cancers.
Topics: Humans; Mitogen-Activated Protein Kinase 11; Mitogen-Activated Protein Kinase 12; Mitogen-Activated Protein Kinase 13; Signal Transduction; Gastrointestinal Neoplasms; p38 Mitogen-Activated Protein Kinases; Tumor Microenvironment
PubMed: 37248432
DOI: 10.1038/s41417-023-00622-1 -
Aging Cell Jul 2023Mitochondrial dysfunction is considered to be an important mediator of the pro-aging process in chronic kidney disease, which is continuously increasing worldwide....
Mitochondrial dysfunction is considered to be an important mediator of the pro-aging process in chronic kidney disease, which is continuously increasing worldwide. Although PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, its role in renal aging remains unclear. We investigated the association between PINK1 and renal aging, especially through the cGAS-STING pathway, which is known to result in an inflammatory phenotype. Pink1 knockout (Pink1 ) C57BL/6 mice and senescence-induced renal tubular epithelial cells (HKC-8) treated with H O were used as the renal aging models. Extensive analyses at transcriptomic-metabolic levels have explored changes in mitochondrial function in PINK1 deficiency. To investigate whether PINK1 deficiency affects renal aging through the cGAS-STING pathway, we explored their expression levels in PINK1 knockout mice and senescence-induced HKC-8 cells. PINK1 deficiency enhances kidney fibrosis and tubular injury, and increases senescence and the senescence-associated secretory phenotype (SASP). These phenomena were most apparent in the 24-month-old Pink1 mice and HKC-8 cells treated with PINK1 siRNA and H O . Gene expression analysis using RNA sequencing showed that PINK1 deficiency is associated with increased inflammatory responses, and transcriptomic and metabolomic analyses suggested that PINK1 deficiency is related to mitochondrial metabolic dysregulation. Activation of cGAS-STING was prominent in the 24-month-old Pink1 mice. The expression of SASPs was most noticeable in senescence-induced HKC-8 cells and was attenuated by the STING inhibitor, H151. PINK1 is associated with renal aging, and mitochondrial dysregulation by PINK1 deficiency might stimulate the cGAS-STING pathway, eventually leading to senescence-related inflammatory responses.
Topics: Animals; Mice; Aging; Kidney; Mice, Inbred C57BL; Nucleotidyltransferases; Protein Kinases
PubMed: 37183600
DOI: 10.1111/acel.13865 -
Cancer Treatment Reviews Sep 2023The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor... (Meta-Analysis)
Meta-Analysis Review
The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, improving survival outcomes compared to endocrine therapy alone. Abemaciclib and ribociclib, in combination with endocrine therapy, have demonstrated significant benefits in invasive disease-free survival for high-risk HR+/HER2- early breast cancer patients. Each CDK4/6i-palbociclib, ribociclib, and abemaciclib-exhibits distinct toxicity profiles. Radiation therapy (RT) can be delivered with a palliative or ablative intent, particularly using stereotactic body radiation therapy for oligometastatic or oligoprogressive disease. However, pivotal randomized trials lack information on concomitant CDK4/6i and RT, and existing preclinical and clinical data on the potential combined toxicities are limited and conflicting. As part of a broader effort to establish international consensus recommendations for integrating RT and targeted agents in breast cancer treatment, we conducted a systematic review and meta-analysis to evaluate the safety profile of combining CDK4/6i with palliative and ablative RT in both metastatic and early breast cancer settings.
Topics: Humans; Female; Radiosurgery; Breast Neoplasms; Cyclin-Dependent Kinases; Cyclin-Dependent Kinase 4; Protein Kinase Inhibitors; Cyclin-Dependent Kinase 6; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37336117
DOI: 10.1016/j.ctrv.2023.102586