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Journal of Clinical Oncology : Official... Sep 2022To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan... (Randomized Controlled Trial)
Randomized Controlled Trial
Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO.
PURPOSE
To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for and wild-type (wt) metastatic colorectal cancer (mCRC).
METHODS
TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable and wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect ≥ 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).
RESULTS
From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, = .526). No differences in early tumor shrinkage rate (57%/58%, = .878) and deepness of response (median: 48%/47%, = .845) were reported, nor in R0 resection rate (25%/29%, = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, = .277).
CONCLUSION
The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with and wt mCRC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Genes, ras; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Prospective Studies; Proto-Oncogene Proteins B-raf; Rectal Neoplasms; ras Proteins
PubMed: 35666229
DOI: 10.1200/JCO.22.00839 -
Cancer Gene Therapy May 2022KRAS is one of the most widely prevalent proto-oncogenes in human cancers. The constitutively active KRAS oncoprotein contributes to both tumor onset and cancer... (Review)
Review
KRAS is one of the most widely prevalent proto-oncogenes in human cancers. The constitutively active KRAS oncoprotein contributes to both tumor onset and cancer development by promoting cell proliferation and anchorage-independent growth in a MAPK pathway-dependent manner. The expression of microRNAs (miRNAs) and the KRAS oncogene are known to be dysregulated in various cancers, while long noncoding RNAs (lncRNAs) can act as regulators of the miRNAs targeting KRAS oncogene in different cancers and have gradually become a focus of research in recent years. In this review article, we summarize recent advances in the research on lncRNAs that have sponging effects on KRAS-targeting miRNAs as crucial mediators of KRAS expression in different cell types and organs. A deeper understanding of lncRNA function in KRAS-driven cancers is of major fundamental importance and will provide a valuable clinical tool for the diagnosis, prognosis, and eventual treatment of cancers.
Topics: Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Proto-Oncogene Proteins p21(ras); RNA, Long Noncoding
PubMed: 34489556
DOI: 10.1038/s41417-021-00381-x -
Blood Mar 2023Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with...
Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eμ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle-associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways.
Topics: Mice; Animals; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins; Proteomics; Lymphoma, B-Cell; Cell Cycle; Proto-Oncogenes; Cell Cycle Proteins; Mitosis
PubMed: 36179280
DOI: 10.1182/blood.2022015494 -
Cancer Metastasis Reviews Dec 2020One of the mechanisms potentially explaining the discrepancy between the number of human genes and the functional complexity of organisms is generating alternative... (Review)
Review
One of the mechanisms potentially explaining the discrepancy between the number of human genes and the functional complexity of organisms is generating alternative splice variants, an attribute of the vast majority of multi-exon genes. Members of the RAS family, such as NRAS, KRAS and HRAS, all of which are of significant importance in cancer biology, are no exception. The structural and functional differences of these splice variants, particularly if they contain the canonical (and therefore routinely targeted for diagnostic purposes) hot spot mutations, pose a significant challenge for targeted therapies. We must therefore consider whether these alternative splice variants constitute a minor component as originally thought and how therapies targeting the canonical isoforms affect these alternative splice variants and their overall functions.
Topics: Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Genes, ras; Humans; Mutation; Neoplasms; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); RNA, Messenger
PubMed: 32772213
DOI: 10.1007/s10555-020-09920-8 -
The FEBS Journal Feb 2022Nucleoli are well defined for their function in ribosome biogenesis, but only a small fraction of the nucleolar proteome has been characterized. Here, we report that the...
Nucleoli are well defined for their function in ribosome biogenesis, but only a small fraction of the nucleolar proteome has been characterized. Here, we report that the proto-oncogene, c-Jun, is targeted to the nucleolus. Using live cell imaging in myogenic cells, we document that the c-Jun basic domain contains a unique, evolutionarily conserved motif that determines nucleolar targeting. Fos family Jun dimer partners, such as Fra2, while nuclear, do not co-localize with c-Jun in the nucleolus. A point mutation in c-Jun that mimics Fra2 (M260E) in its Nucleolar Localization sequence (NoLS) results in loss of c-Jun nucleolar targeting while still preserving nuclear localization. Fra2 can sequester c-Jun in the nucleoplasm, indicating that the stoichiometric ratio of heterodimeric partners regulates c-Jun nucleolar targeting. Finally, nucleolar localization of c-Jun modulates nucleolar architecture and ribosomal RNA accumulation. These studies highlight a novel role for Jun family proteins in the nucleolus, having potential implications for a diverse array of AP-1-regulated cellular processes.
Topics: Amino Acid Sequence; Cell Line; Cell Nucleolus; Fos-Related Antigen-2; Gene Expression Regulation; Genes, jun; Humans; Nuclear Localization Signals; Nuclear Proteins; Protein Transport; Proteome; Ribosomes
PubMed: 34499807
DOI: 10.1111/febs.16187 -
International Journal of Molecular... Sep 2019As an important nongrain crop, the growth and yield of potato ( L.) is often affected by an unfavorable external environment in the process of cultivation. The MYB...
As an important nongrain crop, the growth and yield of potato ( L.) is often affected by an unfavorable external environment in the process of cultivation. The MYB family is one of the largest and most important gene families, participating in the regulation of plant growth and development and response to abiotic stresses. Several genes in potato that regulate anthocyanin synthesis and participate in abiotic stress responses have been identified. To identify all L. () genes involved in hormone or stress responses to potentially regulate potato growth and development, we identified the MYB gene family at the genome-wide level. In this work, 158 genes were found in the potato genome. According to the amino acid sequence of the MYB domain and gene structure, the genes were divided into R2R3-MYB and R1R2R3-MYB families, and the R2R3-MYB family was divided into 20 subgroups (SGs). The expression of 21 genes from different SGs in roots, stems, leaves, flowers, shoots, stolons, young tubers, and mature tubers was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression patterns of genes in potatoes treated with abscisic acid (ABA), indole-3-acetic acid (IAA), gibberellin acid 3 (GA3), NaCl, mannitol, and heat were also measured. We have identified several potential candidate genes that regulate the synthesis of potato flavonoids or participate in hormone or stress responses. This work provides a comprehensive understanding of the MYB family in potato and will lay a foundation for the future investigation of the potential functions of genes in the growth and development of potato.
Topics: Evolution, Molecular; Genes, myb; Genome, Plant; Genome-Wide Association Study; Genomics; Multigene Family; Phylogeny; Plant Development; Plant Growth Regulators; Plant Proteins; Protein Transport; Solanum tuberosum; Stress, Physiological
PubMed: 31569557
DOI: 10.3390/ijms20194847 -
Oncogene May 2023KRAS, HRAS and NRAS proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases....
KRAS, HRAS and NRAS proto-oncogenes belong to a family of 40 highly homologous genes, which in turn are a subset of a superfamily of >160 genes encoding small GTPases. RAS proteins consist of a globular G-domain (aa1-166) and a 22-23 aa unstructured hypervariable region (HVR) that mediates membrane targeting. The evolutionary origins of the RAS isoforms, their HVRs and alternative splicing of the KRAS locus has not been explored. We found that KRAS is basal to the RAS proto-oncogene family and its duplication generated HRAS in the common ancestor of vertebrates. In a second round of duplication HRAS generated NRAS and KRAS generated an additional RAS gene we have designated KRASBL, absent in mammals and birds. KRAS4A arose through a duplication and insertion of the 4 exon of NRAS into the 3 intron of KRAS. We found evolutionary conservation of a short polybasic region (PBR1) in HRAS, NRAS and KRAS4A, a second polybasic region (PBR2) in KRAS4A, two neutralized basic residues (NB) and a serine in KRAS4B and KRASBL, and a modification of the CaaX motif in vertebrates with farnesyl rather than geranylgeranyl polyisoprene lipids, suggesting that a less hydrophobic membrane anchor is critical to RAS protein function. The persistence of four RAS isoforms through >400 million years of evolution argues strongly for differential function.
Topics: Animals; Humans; Proto-Oncogene Proteins p21(ras); Protein Isoforms; ras Proteins; Genes, ras; Mammals
PubMed: 37031342
DOI: 10.1038/s41388-023-02672-z -
Oncotarget Jul 2023Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets... (Review)
Review
Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets for cancer therapy. Despite extensive efforts, targeting Ras proteins with small molecules has been extremely challenging due to Ras's mostly flat surface and lack of small molecule-binding cavities. These challenges were recently overcome by the development of the first covalent small-molecule anti-Ras drug, sotorasib, highlighting the efficacy of Ras inhibition as a therapeutic strategy. However, this drug exclusively inhibits the Ras G12C mutant, which is not a prevalent mutation in most cancer types. Unlike the G12C variant, other Ras oncogenic mutants lack reactive cysteines, rendering them unsuitable for targeting via the same strategy. Protein engineering has emerged as a promising method to target Ras, as engineered proteins have the ability to recognize various surfaces with high affinity and specificity. Over the past few years, scientists have engineered antibodies, natural Ras effectors, and novel binding domains to bind to Ras and counteract its carcinogenic activities via a variety of strategies. These include inhibiting Ras-effector interactions, disrupting Ras dimerization, interrupting Ras nucleotide exchange, stimulating Ras interaction with tumor suppressor genes, and promoting Ras degradation. In parallel, significant advancements have been made in intracellular protein delivery, enabling the delivery of the engineered anti-Ras agents into the cellular cytoplasm. These advances offer a promising path for targeting Ras proteins and other challenging drug targets, opening up new opportunities for drug discovery and development.
Topics: Humans; Genes, ras; ras Proteins; Neoplasms; Mutation; Protein Engineering; Proto-Oncogene Proteins p21(ras)
PubMed: 37395750
DOI: 10.18632/oncotarget.28469 -
Nature Communications Aug 2023Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53...
Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa.
Topics: Animals; Humans; Male; Mice; beta Catenin; Gain of Function Mutation; Oncogene Proteins, Fusion; Prostatic Neoplasms; Proto-Oncogenes; Pyrimidines; Transcriptional Regulator ERG; Tumor Suppressor Protein p53
PubMed: 37537199
DOI: 10.1038/s41467-023-40352-4 -
Blood Aug 2022Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3)...
Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
Topics: Animals; Chromosome Inversion; Chromosomes, Human, Pair 3; DNA-Binding Proteins; Humans; Leukemia, Myeloid, Acute; MDS1 and EVI1 Complex Locus Protein; Mice; Proto-Oncogenes; Transcription Factors
PubMed: 35709354
DOI: 10.1182/blood.2021015325