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Adaptive Resistance Mechanisms in EGFR Mutant NSCLC
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Mariacarmela Santarpia, Niki Karachaliou, Martyna Filipska, Clara Mayo-de-las-Casas, Chiara Lazzari, Maria González-Cao, Rafael Rosell
In a recent work by our group, we demonstrated that lung cancer cells survive initial EGFR inhibitor treatment through activation of, not only STAT3, but also Src-YAP1 signaling, and co-targeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines. High expression of STAT3 or YAP1 predicted worse PFS in two distinct cohorts of EGFR-mutant NSCLC patients treated with first-line EGFR TKIs (Chaib et al., 2017). Co-targeting EGFR, STAT3 and Src-YAP1 with a triple combination was highly synergistic in vitro and in vivo. We have now extended our work to discover that STAT3 but mainly Src-YAP1 are regulatory nodes for the expression of RTKs and non-RTKs. RTKs and non-RTKs are commonly expressed in NSCLC (Rikova et al., 2007). With genetic and pharmacological inhibition, we found that Src family kinases and YAP1 are controlling the expression of RTKs AXL and MET as well as the transmembrane protein CUB-domain containing protein 1 (CDCP1) (Karachaliou et al., 2018). Both AXL and CDCP1 expression were negative predictive factors for treatment with single EGFR TKIs. The combination of gefitinib or osimertinib with a JAK/FAK/Src inhibitor TPX-0005, currently in a phase I/II clinical trial, was synergistic in culture and in xenograft models. We are on the verge of starting a phase I/II study with the combination of osimertinib with TPX-0005 as first-line therapy for metastatic, EGFR mutant NSCLC patients.
Identification of immune-associated prognostic biomarkers in lung adenocarcinoma on the basis of gene co-expression network
Published in Immunopharmacology and Immunotoxicology, 2023
Jianhai Zhang, Ange Chen, Zhang Xue, Chengzhi Liang
High expression of risk factors such as CUB Domain Containing Protein 1 (CDCP1), Inhibitor Of DNA Binding 1 (ID1), and Phospholipid Scramblase 1 (PLSCRI) in the prognostic model led to poor prognosis of LUAD patients. Lately, CDCP1 has been proved to be linked with poor prognoses of patients with breast cancer, colorectal cancer and lung cancer. It is at high level in human colon cancer and lung cancer tissues, and plays a crucial role in cell adhesion or extracellular matrix interaction [28–30]. ID1 is closely associated with tumorigenesis, cell proliferation and survival. It has been proved to be overexpressed in lung cancer, glioblastoma and breast cancer and plays an important role in vital processes [31]. One study found that ID1 may also be an important immunosuppressive target in lung cancer. Iosune Baraibar et al. [32] found that when ID1 expression is inhibited by lung cancer tumor cells, the proportion of CD + T cells in the tumor increases. Enhancing the tumor infiltration degree of CD8 + T cells shows better anti-tumor effect. Abnormally increased expression of PLSCR1 acitivates the Signal Transducer And Activator Of Transcription 1 (STAT1) signaling pathway in breast cancer, ultimately resulting in tumor volume enlargement, tumor deterioration and metastasis [33]. These risk factor genes also play a carcinogenic role in other cancers, which is similar to our results, indicating that the abnormal expression of these genes may promote development of LUAD and might be a potential marker in LUAD progression.
Cabazitaxel-loaded poly(alkyl cyanoacrylate) nanoparticles: toxicity and changes in the proteome of breast, colon and prostate cancer cells
Published in Nanotoxicology, 2021
Anders Øverbye, Maria Lyngaas Torgersen, Tonje Sønstevold, Tore Geir Iversen, Ýrr Mørch, Tore Skotland, Kirsten Sandvig
The increased expression of the downstream SRC target CDCP1 (CUB domain-containing protein 1), would indicate a less favorable effect of SRC-reduction as discussed below. CDCP1 increased approximately 6x and 9x following incubation with free CBZ and PACA-CBZ, respectively. CDCP1 is a transmembrane tetraspanin protein involved in regulation of invasion and metastasis through tyrosine kinases (Orchard-Webb et al. 2014). It is a known substrate for SRC-family kinases which phosphorylates tyrosine residue Y743. It displays high expression in epithelial cells and is proposed as a prognostic unfavorable marker in several cancer types including lung (Ikeda et al. 2009) pancreatic cancer (Uekita et al. 2014), renal cell carcinoma (Awakura et al. 2008; Gao et al. 2013), ovarian cancer (Harrington et al. 2016), and hepatocellular carcinoma (Cao et al. 2016). A feedback loop via CD82/KAI1 from CDCP1 to SRC has been described where increased CDCP1 led to reduced SRC levels (Park et al. 2012).