Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways

Zhu, Shan; Xu, Yan; Wang, Lijun; Liao, Shichong; Wang, Yuan; Shi, Manman; Tu, Yi; Zhou, Yurong; Wen, Wei

doi:10.1186/s12935-020-01735-5

Cited by 16 publications

(12 citation statements)

References 27 publications

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“…Multiple studies suggest that the Ras pathway may influence the behavior of TNBC and HGSOC. For instance, Zhu and colleagues recently reported a correlation between Ras/ERK upregulation and chemoresistance in TNBC [ 70 , 71 ]. In the present series, we could not find any differences in the mutation rate of the Ras signaling pathway-related genes while comparing age and cancer type groups.…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences

Serio

Pereira

Katayama

et al. 2021

Cells

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Background: Triple-negative breast cancer (TNBC) and High-Grade Serous Ovarian Cancer (HGSOC) are aggressive malignancies that share similarities; however, different ages of onset may reflect distinct tumor behaviors. Thus, our aim was to compare somatic mutations in potential driver genes in 109 TNBC and 81 HGSOC from young (Y ≤ 40 years) and elderly (E ≥ 75 years) patients. Methods: Open access mutational data (WGS or WES) were collected for TNBC and HGSOC patients. Potential driver genes were those that were present in the Cancer Gene Census—CGC, the Candidate Cancer Gene Database—CCGD, or OncoKB and those that were considered pathogenic in variant effect prediction tools. Results: Mutational signature 3 (homologous repair defects) was the only gene that was represented in all four subgroups. The median number of mutated CGCs per sample was similar in HGSOC (Y:3 vs. E:4), but it was higher in elderly TNBC than it was in young TNBC (Y:3 vs. E:6). At least 90% of the samples from TNBC and HGSOC from Y and E patients presented at least one known affected TSG. Besides TP53, which was mutated in 67–83% of the samples, the affected TSG in TP53 wild-type samples were NF1 (yHGSOC and yTNBC), PHF6 (eHGSOC and yTNBC), PTEN, PIK3R1 and ZHFX3 (yTNBC), KMT2C, ARID1B, TBX3, and ATM (eTNBC). A few samples only presented one affected oncogene (but no TSG): KRAS and TSHR in eHGSOC and RAC1 and PREX2 (a regulator of RAC1) in yTNBC. At least ⅔ of the tumors presented mutated oncogenes associated with tumor suppressor genes; the Ras and/or PIK3CA signaling pathways were altered in 15% HGSOC and 20–35% TNBC (Y vs. E); DNA repair genes were mutated in 19–33% of the HGSOC tumors but were more frequently mutated in E-TNBC (56%). However, in HGSOC, 9.5% and 3.3% of the young and elderly patients, respectively, did not present any tumors with an affected CGC nor did 4.65% and none of the young and elderly TNBC patients. Conclusion: Most HGSOC and TNBC from young and elderly patients present an affected TSG, mainly TP53, as well as mutational signature 3; however, a few tumors only present an affected oncogene or no affected cancer-causing genes.

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Section: Discussionmentioning

confidence: 99%

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences

Serio

Pereira

Katayama

et al. 2021

Cells

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“…Accordingly, CERK overexpression showed to be a biomarker for chemotherapeutic response in TNBC and higher than two-fold change in CERK (from tumor)/CERK (from normal counterpart) ratio was significantly linked to chemoresistance to doxorubicin and paclitaxel (OR = 2.66, 95% CI 1.18-7.34), p = 0.04. CERK overexpression conferred chemoresistance in TNBC cell lines that CERK inhibition allowed to overcome; mechanistic studies suggest that CERK mediates intrinsic resistance and lower response to CT in TNBC by governing several oncogenic pathways such as Ras (rat sarcoma virus)/ERK (extracellular signal-regulated kinase), PI3K/Akt/mTOR, and Ras homolog family member A (RhoA) [149].…”

Section: Brcanessmentioning

confidence: 99%

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

Scatena

Ghilli

Bargagna

et al. 2022

IJMS

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Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

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“…Of interest, it was also reported that estrogen receptor-negative breast cancer patients with high CERK expression exhibited worse prognosis [ 67 ]. Moreover, CERK overexpression was sufficient to promote triple-negative breast cancer (TNBC) cell growth and migration, and conferred chemoresistance to TNBC cell lines [ 68 ]. Moreover, inhibition of CERK counteracted chemoresistance in the breast cancer cells through a mechanism involving activation of the Ras/ERK, PI3K/Akt/mTOR, and RhoA pathways [ 68 , 69 ].…”

Section: Implication Of Cerk/c1p In Breast Cancermentioning

confidence: 99%

Implication of Ceramide Kinase/C1P in Cancer Development and Progression

Camacho

Ouro

Gómez-Larrauri

et al. 2022

Cancers

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Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible for its biosynthesis, ceramide kinase (CERK), are well established regulators of cell growth and survival in normal, as well as malignant cells through stress-regulated signaling pathways. This metabolite also promotes cell survival, which has been associated with the feedback regulation of other antitumoral sphingolipids or second messengers. C1P also regulates cancer cell invasion and migration of different types of cancer, including lung, breast, pancreas, prostate, or leukemia cells. More recently, CERK and C1P have been implicated in the control of inflammatory responses. The present review provides an updated view on the important role of CERK/C1P in the regulation of cancer cell growth, survival, and dissemination.

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Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways

Cited by 16 publications

References 27 publications

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences

Somatic Mutational Profile of High-Grade Serous Ovarian Carcinoma and Triple-Negative Breast Carcinoma in Young and Elderly Patients: Similarities and Divergences

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

Implication of Ceramide Kinase/C1P in Cancer Development and Progression

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