-
Cancer Chemotherapy and Pharmacology Aug 2023Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug...
A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.
PURPOSE
Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.
METHODS
Patients with actionable somatic mutations or amplifications in ERBB genes or actionable KRAS mutations were enrolled to receive neratinib and trametinib in this phase I dose escalation trial. The primary endpoint was determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary endpoints included pharmacokinetic analysis and preliminary anti-tumor efficacy.
RESULTS
Twenty patients were enrolled with a median age of 50.5 years and a median of 3 lines of prior therapy. Grade 3 treatment-related toxicities included: diarrhea (25%), vomiting (10%), nausea (5%), fatigue (5%) and malaise (5%). The MTD was dose level (DL) minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) given 2 DLTs of grade 3 diarrhea in DL1 (neratinib 160 mg daily with trametinib 1 mg daily). The treatment-related toxicities of DL1 included: diarrhea (100%), nausea (55.6%) and rash (55.6%). Pharmacokinetic data showed trametinib clearance was significantly reduced leading to high drug exposures of trametinib. Two patients achieved stable disease (SD) ≥ 4 months.
CONCLUSION
Neratinib and trametinib combination was toxic and had limited clinical efficacy. This may be due to suboptimal drug dosing given drug-drug interactions.
TRIAL REGISTRATION ID
NCT03065387.
Topics: Humans; Middle Aged; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Protein Kinase Inhibitors; Genes, erbB; Mutation; ErbB Receptors; Nausea; Diarrhea; Mitogen-Activated Protein Kinase Kinases; Receptor, ErbB-2
PubMed: 37314501
DOI: 10.1007/s00280-023-04545-4 -
Oncogene Apr 2022Oncogenic mutations in the small GTPase RAS contribute to ~30% of human cancers. In a Drosophila genetic screen, we identified novel and evolutionary conserved cancer...
Oncogenic mutations in the small GTPase RAS contribute to ~30% of human cancers. In a Drosophila genetic screen, we identified novel and evolutionary conserved cancer genes that affect Ras-driven tumorigenesis and metastasis in Drosophila including confirmation of the tetraspanin Tsp29Fb. However, it was not known whether the mammalian Tsp29Fb orthologue, TSPAN6, has any role in RAS-driven human epithelial tumors. Here we show that TSPAN6 suppressed tumor growth and metastatic dissemination of human RAS activating mutant pancreatic cancer xenografts. Whole-body knockout as well as tumor cell autonomous inactivation using floxed alleles of Tspan6 in mice enhanced Kras-driven lung tumor initiation and malignant progression. Mechanistically, TSPAN6 binds to the EGFR and blocks EGFR-induced RAS activation. Moreover, we show that inactivation of TSPAN6 induces an epithelial-to-mesenchymal transition and inhibits cell migration in vitro and in vivo. Finally, low TSPAN6 expression correlates with poor prognosis of patients with lung and pancreatic cancers with mesenchymal morphology. Our results uncover TSPAN6 as a novel tumor suppressor receptor that controls epithelial cell identify and restrains RAS-driven epithelial cancer.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Cell Transformation, Neoplastic; Genes, ras; Humans; Mammals; Mice; Mutation; Oncogenes; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Tetraspanins
PubMed: 35184157
DOI: 10.1038/s41388-022-02223-y -
Life Science Alliance Nov 2023Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate...
Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate remains unknown. Here, we used the in vitro differentiation of human pluripotent stem cells into cardiomyocytes to study the role of c-JUN. Surprisingly, the knockout of c-JUN improved cardiomyocyte generation, as determined by the number of TNNT2+ cells. ATAC-seq data showed that the c-JUN defect led to increased chromatin accessibility on critical regulatory elements related to cardiomyocyte development. ChIP-seq data showed that the knockout c-JUN increased RBBP5 and SETD1B expression, leading to improved H3K4me3 deposition on key genes that regulate cardiogenesis. The c-JUN KO phenotype could be copied using the histone demethylase inhibitor CPI-455, which also up-regulated H3K4me3 levels and increased cardiomyocyte generation. Single-cell RNA-seq data defined three cell branches, and knockout c-JUN activated more regulons that are related to cardiogenesis. In summary, our data demonstrated that c-JUN could regulate cardiomyocyte cell fate by modulating H3K4me3 modification and chromatin accessibility and shed light on how c-JUN regulates heart development in humans.
Topics: Animals; Humans; Mice; Cell Differentiation; Chromatin; Genes, jun; Human Embryonic Stem Cells; Myocytes, Cardiac; Proto-Oncogene Proteins c-jun
PubMed: 37604584
DOI: 10.26508/lsa.202302121 -
Journal of Cell Science Oct 2020The Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to... (Review)
Review
The Ras oncogene is notoriously difficult to target with specific therapeutics. Consequently, there is interest to better understand the Ras signaling pathways to identify potential targetable effectors. Recently, the mechanistic target of rapamycin complex 2 (mTORC2) was identified as an evolutionarily conserved Ras effector. mTORC2 regulates essential cellular processes, including metabolism, survival, growth, proliferation and migration. Moreover, increasing evidence implicate mTORC2 in oncogenesis. Little is known about the regulation of mTORC2 activity, but proposed mechanisms include a role for phosphatidylinositol (3,4,5)-trisphosphate - which is produced by class I phosphatidylinositol 3-kinases (PI3Ks), well-characterized Ras effectors. Therefore, the relationship between Ras, PI3K and mTORC2, in both normal physiology and cancer is unclear; moreover, seemingly conflicting observations have been reported. Here, we review the evidence on potential links between Ras, PI3K and mTORC2. Interestingly, data suggest that Ras and PI3K are both direct regulators of mTORC2 but that they act on distinct pools of mTORC2: Ras activates mTORC2 at the plasma membrane, whereas PI3K activates mTORC2 at intracellular compartments. Consequently, we propose a model to explain how Ras and PI3K can differentially regulate mTORC2, and highlight the diversity in the mechanisms of mTORC2 regulation, which appear to be determined by the stimulus, cell type, and the molecularly and spatially distinct mTORC2 pools.
Topics: Animals; Class I Phosphatidylinositol 3-Kinases; Genes, ras; Humans; Mechanistic Target of Rapamycin Complex 2; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 33033115
DOI: 10.1242/jcs.234930 -
Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer.Cancer Discovery Dec 2021Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel...
UNLABELLED
Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf-Mycl-driven mouse model of SCLC. RLF-MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF-MYCL genetically engineered mouse model displayed gene expression similarities with human RLF-MYCL SCLC. Together, our studies support RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC.
SIGNIFICANCE
The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF-MYCL gene fusion by developing a Rlf-Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Gene Fusion; Genes, myc; Lung Neoplasms; Mice; Proto-Oncogene Proteins c-myc; Small Cell Lung Carcinoma; Telomere-Binding Proteins
PubMed: 34344693
DOI: 10.1158/2159-8290.CD-21-0441 -
Clinical and Translational Medicine Aug 2022
Topics: Ferroptosis; Genes, myc; Humans; N-Myc Proto-Oncogene Protein; Neuroblastoma
PubMed: 35908258
DOI: 10.1002/ctm2.963 -
Nature Communications Jan 2024Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic...
Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins p21(ras); Allelic Imbalance; Genes, ras; Cell Transformation, Neoplastic; Colorectal Neoplasms; Mutation; Tumor Microenvironment
PubMed: 38168062
DOI: 10.1038/s41467-023-44342-4 -
The Journal of Biological Chemistry Oct 2022Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of...
Family with sequence similarity 83 A (FAM83A) is a newly discovered proto-oncogene that has been shown to play key roles in various cancers. However, the function of FAM83A in other physiological processes is not well known. Here, we report a novel function of FAM83A in adipocyte differentiation. We used an adipocyte-targeting fusion oligopeptide (FITC-ATS-9R) to deliver a FAM83A-sgRNA/Cas9 plasmid to knockdown Fam83a (ATS/sg-FAM83A) in white adipose tissue in mice, which resulted in reduced white adipose tissue mass, smaller adipocytes, and mitochondrial damage that was aggravated by a high-fat diet. In cultured 3T3-L1 adipocytes, we found loss or knockdown of Fam83a significantly repressed lipid droplet formation and downregulated the expression of lipogenic genes and proteins. Furthermore, inhibition of Fam83a decreased mitochondrial ATP production through blockage of the electron transport chain, associated with enhanced apoptosis. Mechanistically, we demonstrate FAM83A interacts with casein kinase 1 (CK1) and promotes the permeability of the mitochondrial outer membrane. Furthermore, loss of Fam83a in adipocytes hampered the formation of the TOM40 complex and impeded CK1-driven lipogenesis. Taken together, these results establish FAM83A as a critical regulator of mitochondria maintenance during adipogenesis.
Topics: Animals; Mice; 3T3-L1 Cells; Adipocytes, White; Adipogenesis; Casein Kinase I; Cell Differentiation; Mitochondria; Proto-Oncogenes; Neoplasm Proteins
PubMed: 35931121
DOI: 10.1016/j.jbc.2022.102339 -
Molecules (Basel, Switzerland) Jan 2023Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However,... (Review)
Review
Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However, for its high-risk type, even with various intensive treatment options, the prognosis is still unsatisfactory. At the same time, a large number of research data show that the abnormal amplification and high-level expression of the gene are positively correlated with the malignant progression, poor prognosis, and mortality of neuroblastoma. In this context, this article explores the role of the N-Myc, gene expression product on its target genes related to the cell cycle and reveals its regulatory network in promoting tumor proliferation and malignant progression. We hope it can provide ideas and direction for the research and development of drugs targeting N-Myc and its downstream target genes.
Topics: Humans; Nuclear Proteins; N-Myc Proto-Oncogene Protein; Genes, myc; Cell Cycle; Neuroblastoma; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 36770809
DOI: 10.3390/molecules28031141 -
Journal of Advanced Research Dec 2023Aberrations in MYC underlie a large proportion of liver hepatocellular carcinoma (LIHC) cases; however, MYC is difficult to target because of its undruggable structure....
BACKGROUND
Aberrations in MYC underlie a large proportion of liver hepatocellular carcinoma (LIHC) cases; however, MYC is difficult to target because of its undruggable structure. We aimed to uncover MYC-associated molecular targets to provide new strategies for LIHC treatment.
METHODS
LIHC transcriptome datasets and clinical information were obtained from The Cancer Genome Atlas. A series of bioinformatics analyses were performed for 370 patients who were stratified based on the median MYC expression level (high-MYC group and low-MYC group). Correlation analysis was performed to determine relationships between the expression of key MYC-associated genes and prognosis, DNA promotor methylation, and immune cell infiltration. Gene ontology and Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analyses were performed to elucidate the functions of these genes in LIHC. Their expression and functions in LIHC were further verified using transgenic mice overexpressing c-Myc under control of the hepatocyte-specific promoter (Alb-Cre).
RESULTS
AURKB, CCNB2, and CDKN3 were overexpressed in LIHC patients with high MYC expression and were associated with poor prognosis. Upregulation of these 3 genes was significantly correlated with hypomethylated promoter status, advanced T stage, metastasis, and immune cell infiltration in LIHC patients. Functional enrichment analyses indicated that these genes participate in the "p53 signaling pathway" and "cell cycle". Furthermore, RT-PCR and IHC analysis revealed that their mRNA and protein expression levels were upregulated in an Alb-Cre;cMYC mouse model. Drugs that target these 3 MYC-related genes were identified.
CONCLUSION
Taken together, our results identify biomarkers of potential utility for managing liver cancer therapy owing to their significance in tumorigenesis, proliferation, and tumor immunity.
Topics: Animals; Mice; Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Genes, myc; Genes, cdc
PubMed: 36716957
DOI: 10.1016/j.jare.2023.01.010