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Cancer Discovery Sep 2023Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular...
UNLABELLED
Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.
SIGNIFICANCE
In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K-mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.
Topics: Humans; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases; Class I Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinases
PubMed: 37377403
DOI: 10.1158/2159-8290.CD-22-1441 -
Nature Nov 2023Timely repair of chromosomal double-strand breaks is required for genome integrity and cellular viability. The polymerase theta-mediated end joining pathway has an...
Timely repair of chromosomal double-strand breaks is required for genome integrity and cellular viability. The polymerase theta-mediated end joining pathway has an important role in resolving these breaks and is essential in cancers defective in other DNA repair pathways, thus making it an emerging therapeutic target. It requires annealing of 2-6 nucleotides of complementary sequence, microhomologies, that are adjacent to the broken ends, followed by initiation of end-bridging DNA synthesis by polymerase θ. However, the other pathway steps remain inadequately defined, and the enzymes required for them are unknown. Here we demonstrate requirements for exonucleolytic digestion of unpaired 3' tails before polymerase θ can initiate synthesis, then a switch to a more accurate, processive and strand-displacing polymerase to complete repair. We show the replicative polymerase, polymerase δ, is required for both steps; its 3' to 5' exonuclease activity for flap trimming, then its polymerase activity for extension and completion of repair. The enzymatic steps that are essential and specific to this pathway are mediated by two separate, sequential engagements of the two polymerases. The requisite coupling of these steps together is likely to be facilitated by physical association of the two polymerases. This pairing of polymerase δ with a polymerase capable of end-bridging synthesis, polymerase θ, may help to explain why the normally high-fidelity polymerase δ participates in genome destabilizing processes such as mitotic DNA synthesis and microhomology-mediated break-induced replication.
Topics: DNA; DNA End-Joining Repair; DNA Polymerase III; DNA-Directed DNA Polymerase; Genomic Instability; DNA Polymerase theta
PubMed: 37968395
DOI: 10.1038/s41586-023-06729-7 -
Immunity Apr 2024RIG-I-like receptors (RLRs) are crucial for pathogen detection and triggering immune responses and have immense physiological importance. In this review, we first... (Review)
Review
RIG-I-like receptors (RLRs) are crucial for pathogen detection and triggering immune responses and have immense physiological importance. In this review, we first summarize the interferon system and innate immunity, which constitute primary and secondary responses. Next, the molecular structure of RLRs and the mechanism of sensing non-self RNA are described. Usually, self RNA is refractory to the RLR; however, there are underlying host mechanisms that prevent immune reactions. Studies have revealed that the regulatory mechanisms of RLRs involve covalent molecular modifications, association with regulatory factors, and subcellular localization. Viruses have evolved to acquire antagonistic RLR functions to escape the host immune reactions. Finally, the pathologies caused by the malfunction of RLR signaling are described.
Topics: DEAD-box RNA Helicases; Interferon-Induced Helicase, IFIH1; DEAD Box Protein 58; Signal Transduction; Immunity, Innate; Receptors, Immunologic; RNA
PubMed: 38599168
DOI: 10.1016/j.immuni.2024.03.003 -
Molecular Cell Nov 2023Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs and global gene expression...
Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells.
Topics: Humans; Cyclin-Dependent Kinases; Cyclin-Dependent Kinase-Activating Kinase; Signal Transduction; Cell Cycle; Enzyme Inhibitors; TOR Serine-Threonine Kinases; Neoplasms; Cell Line, Tumor
PubMed: 37977119
DOI: 10.1016/j.molcel.2023.10.017 -
Nature Sep 2023DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair...
DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle. In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination. However, these pathways are completely inhibited in mitosis, leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity.
Topics: Humans; BRCA1 Protein; Cell Cycle Proteins; Cell Death; DNA Breaks, Double-Stranded; DNA Repair; DNA-Directed DNA Polymerase; Homologous Recombination; Mitosis; Phosphorylation; Protein Serine-Threonine Kinases; Synthetic Lethal Mutations; DNA Polymerase theta; Polo-Like Kinase 1
PubMed: 37674080
DOI: 10.1038/s41586-023-06506-6 -
Biochimica Et Biophysica Acta. Reviews... Nov 2023The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a key pathway through which the host regulates immune responses by... (Review)
Review
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a key pathway through which the host regulates immune responses by recognizing cytoplasmic double-stranded DNA of abnormal origin, and it plays an important role in tumor growth as well as metastasis, with relevant molecular details constantly being explored and updated. The significant immunomodulatory effects make STING an attractive target for cancer immunotherapy, and STING agonists have been receiving great attention for their development and clinical translation. Despite exciting results in preclinical work, the application of STING agonists to cancer therapy remains challenging due to their poor pharmacokinetic and physicochemical properties, as well as toxic side effects they produce. Here, we summarize the dichotomous role of cGAS-STING in cancer and discuss the limitations of cancer immunotherapy based on STING activation as well as feasible strategies to overcome them to achieve tumor regression.
Topics: Humans; Neoplasms; Signal Transduction; Nucleotidyltransferases; DNA
PubMed: 37717857
DOI: 10.1016/j.bbcan.2023.188983 -
Phytomedicine : International Journal... Jan 2024Banxia Xiexin decoction (BXD) is a traditional Chinese medicine with anti-colorectal cancer (CRC) activity. However, its bioactive constituents and its mechanism of...
BACKGROUND
Banxia Xiexin decoction (BXD) is a traditional Chinese medicine with anti-colorectal cancer (CRC) activity. However, its bioactive constituents and its mechanism of action remain unclear. Herein, we explored the mechanism of action of BXD against CRC using a network pharmacology approach.
METHODS
First, the targets of the main chemical components of BXD were predicted and collected through a database, and the intersection of compound targets and disease targets was obtained. Subsequently, protein-protein interaction network analysis, Gene Ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to explore the potential mechanisms underlying the effects of BXD on CRC. Finally, a CRC cell model and a CRC xenograft model in nude mice were utilized to further determine the mechanism of action.
RESULTS
A compound-therapeutic target network of BXD was constructed, revealing 146 cellular targets of BXD. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling axis was identified as the main target of BXD. Using in vitro and in vivo models, the activity of BXD against CRC was found to be mediated through ferritinophagy by targeting the PI3K/AKT/mTOR axis, leading to intracellular iron accumulation, reactive oxygen species activation, and finally ferroptosis.
CONCLUSIONS
Through the application of network pharmacology and in vitro/in vivo validation experiments, we discovered that BXD exerts anti-CRC effects via the ferritinophagy pathway. Furthermore, we elucidated the potential mechanism underlying its induction of ferritinophagy. These findings demonstrate the significant potential of traditional drugs in managing CRC and support their wider clinical application in combination chemotherapy, targeted therapy, and immunotherapy.
Topics: Animals; Mice; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Mice, Nude; Network Pharmacology; Drugs, Chinese Herbal; Phosphatidylinositol 3-Kinase; TOR Serine-Threonine Kinases; Colorectal Neoplasms; Molecular Docking Simulation; Mammals
PubMed: 38039904
DOI: 10.1016/j.phymed.2023.155174 -
International Journal of Molecular... Aug 2023Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The... (Review)
Review
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
Topics: Humans; Pulmonary Arterial Hypertension; Endothelial Cells; Familial Primary Pulmonary Hypertension; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit
PubMed: 37628831
DOI: 10.3390/ijms241612653 -
The Journal of Experimental Medicine Nov 2023Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to...
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.
Topics: Humans; Animals; Mice; Female; Breast Neoplasms; MTOR Inhibitors; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 37642941
DOI: 10.1084/jem.20211743 -
ELife Dec 2023Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Topics: Leishmania donovani; Ligands; Phosphotransferases; Cyclic AMP-Dependent Protein Kinases; Purine Nucleosides; Trypanosoma brucei brucei
PubMed: 38126364
DOI: 10.7554/eLife.94720