p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors

Grassilli, Emanuela; Cerrito, Maria Grazia; Bonomo, Sara; Giovannoni, Roberto; Conconi, Donatella; Lavitrano, Marialuisa

doi:10.3389/fcell.2021.690365

Cited by 9 publications

(9 citation statements)

References 68 publications

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“…The efficacy of other agents in mCHT treatment combined with antiangiogenic treatment should be investigated. An example of a promising approach is the use of Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib, which was developed to treat several blood cancers, but has recently been shown to act effectively in solid tumours [ 68 , 69 ]. These drugs hit multiple targets and are associated with numerous expected outcomes.…”

Section: Discussionmentioning

confidence: 99%

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Cazzaniga

Capici²,

Cordani

et al. 2022

JCM

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Metronomic chemotherapy (mCHT), defined as continuous administration of low-dose chemotherapeutic agents with no or short regular treatment-free intervals, was first introduced to the clinic in international guidelines in 2017, and, since then, has become one of the available strategies for the treatment of advanced breast cancer (ABC). Despite recent successes, many unsolved practical and theoretical issues remain to be addressed. The present review aims to identify the “lights and shadows” of mCHT in preclinical and clinical settings. In the preclinical setting, several findings indicate that one of the most noticeable effects of mCHT is on the tumor microenvironment, which, over the last twenty years, has been demonstrated to be pivotal in supporting tumor cell survival and proliferation. On the other hand, the direct effects on tumor cells have been less well-defined. In addition, critical items to be addressed are the lack of definition of an optimal biological dose (OBD), the method of administration of metronomic schedules, and the recognition and validation of predictive biomarkers. In the clinical context—where mCHT has mainly been used in a metastatic setting—low toxicity is the most well-recognised light of mCHT, whereas the type of study design, the absence of randomised trials and uncertainty in terms of doses and drugs remain among the shadows. In conclusion, growing evidence indicates that mCHT is a suitable treatment option for selected metastatic breast cancer (MBC) patients. Moreover, given its multimodal mechanisms of action, its addition to immunological and targeted therapies might represent a promising new approach to the treatment of MBC. More preclinical data are needed in this regard, which can only be obtained through support for translational research as the key link between basic science and patient care.

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Section: Discussionmentioning

confidence: 99%

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Cazzaniga

Capici²,

Cordani

et al. 2022

JCM

Self Cite

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“…Lyn gene is a primary regulator of various signal transduction pathways and is involved in the occurrence of a variety of malignant tumors [14]. BTK is a potent oncogene that plays a role in the downstream RAS/MAPK pathway and is essential for RAS-mediated transformation [15]. PIK3CA gene is a candidate driver gene for lung squamous cell carcinoma, which may be involved in tumor cell growth and the development of non-small cell lung cancer [16].…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characteristics, transcriptome, and drug efficacy of ERBB2 tyrosine kinase and non-tyrosine kinase mutations in non-small cell lung cancer

Zheng

Ying

et al. 2023

Preprint

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ERBB2 mutations in the tyrosine kinase domain (TKD) have been widely reported in non-small cell lung cancer (NSCLC). More and more non-tyrosine kinase domain (non-TKD) mutations of ERBB2 have been detected. However, the clinical effects of non-TKD mutations are still unknown. Therefore, this study aims to study the molecular and clinical characteristics, transcriptome differences, and sensitive drugs of TKD and non-TKD mutations in NSCLC. Gene mutation, RNA sequencing, and clinical information of NSCLC with ERBB2 mutations were downloaded. Bioinformatics methods, such as gene mutation analysis, differentially expressed genes (DEGs), functional enrichment analysis, protein-protein interaction (PPI), hub gene identification, and drug sensitivity analysis, were adopted. Finally, four patients were included to reflect the treatment response. The somatic mutation rate of ERBB2 was 3.2%. TKD and non-TKD mutations mainly occurred in lung adenocarcinoma. Non-TKD mutations have a better prognosis. Up-regulated DEGs are primarily involved in immune and inflammatory pathways. We then proved that BTK, LYN, and PIK3CA mutations have a better prognosis than wild type in patients of NSCLC. The drug sensitivity study found that the TKD group was more sensitive to 5 drugs, and the non-TKD was 28.TKD and non-TKD mutations identify two independent subsets of ERBB2 mutations in NSCLC. Non-TKD mutations have a better prognosis and can also be used as targets for ERBB2. Our study can provide a foundation for further clinical research, highlighting the importance of individualized treatment for patients with different mutation domains.

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“…Further studies from our lab indicate p65BTK as an actionable target in different solid tumors other than CRC. In fact, preclinical data indicate that depending on the tumor type, BTK inhibitors used alone can induce cytotoxicity in gliomas [ 52 ] , be more effective than standard-of-care (SOC) chemotherapy in drug-resistant ovarian cancer [ 53 ] or can kill drug-resistant tumor cells when used in combination with SOC chemotherapy or targeted therapy in non-small-cell lung cancer [ 54 ] , and melanomas (unpublished data).…”

Section: Resistance To Chemotherapymentioning

confidence: 99%

Emerging actionable targets to treat therapy-resistant colorectal cancers

Grassilli¹,

Cerrito²

2022

CDR

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In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a “big killer” mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

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p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors

Cited by 9 publications

References 68 publications

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows

Clinical and molecular characteristics, transcriptome, and drug efficacy of ERBB2 tyrosine kinase and non-tyrosine kinase mutations in non-small cell lung cancer

Emerging actionable targets to treat therapy-resistant colorectal cancers

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