Drugging KRAS: current perspectives and state-of-art review

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Oct. 25, 2022

Abstract After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the ‘holy grail’ targeted cancer therapies, is most frequently mutated oncogene human Under normal conditions, shuttles between GDP-bound ‘off’ state and GTP-bound ‘on’ state. Mutant constitutively activated leads to persistent downstream signaling oncogenesis. In 2013, improved understanding biology newer drug designing technologies led crucial discovery a cysteine drug-binding pocket mutant G12C protein. Covalent inhibitors that block were successfully developed sotorasib was first inhibitor be approved, with more pipeline. Simultaneously, effects on tumour microenvironment also discovered, partly owing universal use immune checkpoint inhibitors. this review, discuss discovery, biology, function We relationship microenvironment, therapeutic strategies target KRAS. Finally, review current clinical evidence ongoing trials novel agents shine light resistance pathways known so far.

Language: Английский

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The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer

Annals of Oncology, Journal Year: 2022, Volume and Issue: 33(12), P. 1269 - 1283

Published: Sept. 9, 2022

Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for genomic profiling that overcomes many limitations traditional tissue-based analysis. We examined cfDNA as a tool to inform patients with BTC and generate novel insights into tumor biology.We analyzed next-generation sequencing data 2068 samples from 1671 generated Guardant360. carried out annotation on multi-institutional subset (n = 225) assess intra-patient cfDNA-tumor concordance the association variant allele fraction (VAF) outcomes.Genetic alterations were detected in 84% patients, targetable 44% patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, BRAF V600E clonal majority cases, affirming these early driver events BTC. Concordance between tissue mutation detection was high IDH1 mutations (87%) (100%), low FGFR2 fusions (18%). uncovered putative mechanisms resistance targeted therapies, including cysteine residue (FGFR2 C492F) which covalent FGFR inhibitors bind. High pre-treatment VAF associated poor prognosis shorter response chemotherapy therapy. Finally, we report frequency promising targets currently under investigation other solid tumors, KRAS G12C (1.0%), G12D (5.1%), PIK3CA (6.8%), ERBB2 amplifications (4.9%).These findings largest most comprehensive study date highlight utility current this disease. Characterization oncogenic drivers therapeutic will drug development efforts reduce mortality

Language: Английский

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Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 6, 2023

Abstract HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor activation and has activity -mutant tumours. SUMMIT is open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib patients solid tumours harbouring oncogenic somatic (ClinicalTrials.gov: NCT01953926). The primary objective the BTC cohort, which now complete, first response rate (ORR) to 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration response, overall safety tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), ORR 16% (95% CI 4.5–36.1%). most common S310F (n = 11; 48%) V777L 4; 17%). Outcomes appear worse for or those co-occurring TP53 CDKN2A alterations. Loss amplified acquisition multiple previously undetected co-mutations identified at progression one responder. Diarrhoea adverse event, any-grade diarrhoea 14 (56%). Although demonstrates antitumour refractory mutations, endpoint was not met combinations may be explored.

Language: Английский

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Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma

American Journal of Transplantation, Journal Year: 2021, Volume and Issue: 22(3), P. 823 - 832

Published: Dec. 2, 2021

Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed protocol therapy and patients with locally advanced, unresectable iCCA in 2010. Patients undergoing were required demonstrate disease stability 6 months on no extrahepatic disease. During the study period, 32 listed 18 underwent LT. For transplanted patients, median number of tumors was 2, cumulative tumor diameter 10.4 cm. receiving had an overall survival at 1-, 3-, 5-years 100%, 71%, 57%. Recurrences occurred seven treated systemic resection. The population higher than expected proportion genetic alterations fibroblast growth factor receptor (FGFR) DNA damage repair pathways. These data support as treatment highly selected iCCA. Further studies identify criteria factors predicting are warranted.

Language: Английский

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Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma

Frontiers in Medicine, Journal Year: 2022, Volume and Issue: 9

Published: March 31, 2022

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with increasing incidence worldwide. Recently, histopathologic classification of small duct type and large iCCA has been introduced. Both these types tumors exhibit differences in clinicopathological features, mutational profiles, prognosis. Small composed non-mucin-producing cuboidal cells, whereas mucin-producing columnar reflecting different cells origin. Large shows more invasive growth poorer prognosis than iCCA. The background often chronic disease related to hepatitis B or C viral infection, alcoholic non-alcoholic fatty disease/steatohepatitis, contrast that hepatolithiasis fluke infection. Cholangiolocarcinoma a variant naïve-looking forming cords ductule-like structures, better the conventional type. Fibrous tumor stroma, one characteristic features iCCA, contains activated fibroblasts intermixed innate adaptive immune cells. stroma (mature versus immature) are behavior Low tumor-infiltrating lymphocyte density, KRAS alteration, chromosomal instability immune-suppressive microenvironments resistance programmed death 1/ ligand 1 blockade. Data from recent large-scale exome analyses have revealed heterogeneity molecular profiles showing frequent BAP1 , IDH1/2 hotspot mutations FGFR2 fusion, TP53 SMAD4 observed Multi-omics proposed several classifications including inflammation class proliferation class. enriched inflammatory signaling pathways expression cytokines, while oncogenic pathways. Diverse pathologic its associated multi-omics characteristics currently under active investigation, thereby providing insights into precision therapeutics for patients This review provides latest knowledge on ranging microenvironment genomic transcriptomic research.

Language: Английский

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Molecular Subgroups of Intrahepatic Cholangiocarcinoma Discovered by Single-Cell RNA Sequencing–Assisted Multiomics Analysis

Cancer Immunology Research, Journal Year: 2022, Volume and Issue: 10(7), P. 811 - 828

Published: May 20, 2022

Abstract Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly aggressive tumor type that responds poorly to chemotherapy and immunotherapy. Comprehensive molecular characterization of ICC essential for the development novel therapeutics. Here, we constructed two independent cohorts from clinic centers. A comprehensive multiomics analysis via proteomic, whole-exome sequencing (WES), single-cell RNA (scRNA-seq) was performed. Novel subtypes were derived in training cohort (n = 110) using proteomic signatures their associated activated pathways, which further validated validation 41). Three subtypes, chromatin remodeling, metabolism, chronic inflammation, with distinct prognoses identified. The inflammation subtype poor prognosis. Our random forest algorithm revealed mutation lysine methyltransferase 2D (KMT2D) frequently occurred metabolism lower inflammatory activity. scRNA-seq identified an APOE+C1QB+ macrophage subtype, showed capacity reshape contribute prognosis ICC. Altogether, transcriptome-assisted analysis, tumor-associated macrophages as potential immunotherapy targets against

Language: Английский

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Rational development of combination therapies for biliary tract cancers

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 78(1), P. 217 - 228

Published: Sept. 20, 2022

Language: Английский

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Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma

JAMA Surgery, Journal Year: 2022, Volume and Issue: 157(7), P. 590 - 590

Published: May 11, 2022

Intrahepatic cholangiocarcinoma (iCCA) is often multifocal (ie, satellites or intrahepatic metastases) at presentation.

Language: Английский

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Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives

Cancers, Journal Year: 2024, Volume and Issue: 16(15), P. 2752 - 2752

Published: Aug. 2, 2024

The isocitrate dehydrogenase 1 and 2 (IDH1 IDH2) enzymes are involved in key metabolic processes human cells, regulating differentiation, proliferation, oxidative damage response. IDH mutations have been associated with tumor development progression various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, other types become crucial markers molecular classification prognostic assessment. intratumoral serum levels of D-2-hydroxyglutarate (D-2-HG) could serve diagnostic biomarkers for identifying mutant (IDHmut) tumors. As a result, an increasing number clinical trials evaluating targeted treatments IDH1/IDH2 mutations. Recent studies shown that the focus these new therapeutic strategies is not only neomorphic activity IDHmut but also epigenetic shift induced by potential role combination treatments. Here, we provide overview current knowledge about tumors, particular on available IDH-targeted emerging results from aiming to explore tumor-specific features identify benefit therapies their strategies. An insight into future perspectives roles circulating radiomic included.

Language: Английский

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Association of BRAF Variants With Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma

JAMA Network Open, Journal Year: 2023, Volume and Issue: 6(3), P. e231476 - e231476

Published: March 3, 2023

Importance BRAF variants are associated with tumor progression; however, the prevalence of variant subtypes and their association disease characteristics, prognosis, targeted therapy response in patients intrahepatic cholangiocarcinoma (ICC) largely unknown. Objective To explore ICC. Design, Setting, Participants In this cohort study, 1175 who underwent curative resection for ICC from January 1, 2009, through December 31, 2017, were evaluated at a single hospital China. Whole-exome sequencing, Sanger sequencing performed to identify variants. The Kaplan-Meier method log-rank test used compare overall survival (OS) disease-free (DFS). Univariate multivariate analyses using Cox proportional hazards regression. Associations between tested 6 -variant, patient-derived organoid lines 3 patient donors those lines. Data analyzed June 2021, March 15, 2022. Interventions Hepatectomy Main Outcomes Measures OS DFS. Results Of ICC, mean (SD) age was 59.4 (10.4) years 701 (59.7%) men. A total 20 different somatic variance affecting 49 (4.2%) identified; V600E most frequent allele cohort, accounting 27% identified variants, followed by K601E (14%), D594G (12%), N581S (6%). Compared non-V600E more likely have large size (10 13 [77%] vs 12 36 [33%]; P = .007), multiple tumors (7 [54%] 8 [22%]; .04), vascular/bile duct invasion .04). Multivariate analysis revealed that but not or poor (hazard ratio [HR], 1.87; 95% CI, 1.05-3.33; .03) DFS (HR, 1.66; 1.03-2.97; There also broad differences among organoids sensitivity MEK inhibitors. Conclusions Relevance findings study suggest there Identifying classifying may be able help guide precise treatment

Language: Английский

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