Presence of MET exon 14 skipping and fusion as mechanism of osimertinb resistance in a lung adenocarcinoma with an EGFR exon 19 deletion that responds to combination of capmatinib and osimertinb: A case report.

Lung cancer stands as a leading cause of mortality in China, with EGFR mutations frequently identified as pivotal driver genes. Osimertinib, a tyrosine kinase inhibitor targeting EGFR mutations, is typically employed as a first-line treatment for EGFR-sensitive mutations; nevertheless, resistance can emerge. In this case report, we present the case of a 53-year-old non-smoking male diagnosed with stage IV lung adenocarcinoma bearing an EGFR exon 19 deletion. This patient eventually developed resistance to both Erlotinib and Osimertinib after 28 months of treatment. Subsequent genetic testing uncovered the emergence of new MET exon 14 skipping and MET fusion, coexisting with the initial EGFR exon 19 deletion. In light of this complex molecular profile, the patient was administered a combination therapy consisting of Osimertinib and Capmatinib. This novel approach yielded a partial response, and notably, the patient experienced a progression-free survival exceeding 7 months. Vigilant monitoring of the patient's progress revealed the disappearance of the MET exon 14 skipping and a notable improvement in the patient's symptoms. This case report underscores the potential efficacy of Osimertinib and Capmatinib combination therapy as a viable treatment strategy for patients harboring EGFR-mutated lung cancer who develop resistance to first-line EGFR inhibitors due to MET activation.

ILP-2: A New Bane and Therapeutic Target for Human Cancers.

Inhibitor of apoptosis protein-related-like protein-2 (ILP-2), also known as BIRC-8, is a member of the inhibitor of apoptosis protein (IAPs) family, which mainly encodes the negative regulator of apoptosis. It is selectively overexpressed in a variety of human tumors and can help tumor cells evade apoptosis, promote tumor cell growth, increase tumor cell aggressiveness, and appears to be involved in tumor cell resistance to chemotherapeutic drugs. Several studies have shown that downregulation of ILP-2 expression increases apoptosis, inhibits metastasis, reduces cell growth potential, and sensitizes tumor cells to chemotherapeutic drugs. In addition, ILP-2 inhibits apoptosis in a unique manner; it does not directly inhibit the activity of caspases but induces apoptosis by cooperating with other apoptosis-related proteins. Here, we review the current understanding of the various roles of ILP-2 in the apoptotic cascade and explore the use of interfering ILP-2, and the combination of related anti-tumor agents, as a novel strategy for cancer therapy.

Proteomic analysis of inhibitor of apoptosis protein­like protein­2 on breast cancer cell proliferation.

Although inhibitor of apoptosis protein­like protein­2 (ILP­2) is considered to be a novel enhancer of breast cancer proliferation, its underlying mechanism of action remains unknown. Therefore, the present study aimed to investigate the expression profile of ILP­2­related proteins in MCF­7 cells to reveal their effect on promoting breast cancer cell proliferation. The isobaric tags for relative and absolute quantification (iTRAQ) method was used to analyse the expression profile of ILP­2­related proteins in MCF­7 breast cancer cells transfected with small interfering (si)RNA against ILP­2 (siRNA­5 group) and the negative control (NC) siRNA. The analysis of the iTRAQ data was carried out using western blotting and reverse transcription­quantitative PCR. A total of 4,065 proteins were identified in MCF­7 cells, including 241 differentially expressed proteins (DEPs; fold change ≥1.20 or ≤0.83; P<0.05). Among them, 156 proteins were upregulated and 85 were downregulated in the siRNA­5 group compared with in the NC group. The aforementioned DEPs were mainly enriched in 'ECM­receptor interaction'. In addition, the top 10 biological processes related to these proteins were associated with signal transduction, cell proliferation and immune system processes. Furthermore, ILP­2 silencing upregulated N(4)­(ß­N­acetylglucosaminyl)­L­asparaginase, metallothionein­1E and tryptophan 2,3­dioxygenase, whereas ILP­2 overexpression exerted the opposite effect. The results of the present study suggested that ILP­2 could promote breast cancer growth via regulating cell proliferation, signal transduction, immune system processes and other cellular physiological activities.

Inhibitor of apoptosis protein­like protein­2: A novel growth accelerator for breast cancer cells.

Although the inhibitor of apoptosis protein­like protein­2 (ILP­2) has been shown as a serological biomarker for breast cancer, its effect on breast cancer cell growth remains elusive. The present study aimed to determine the role of ILP­2 in breast cancer cell growth. We used immunohistochemistry to analyze ILP­2 expression in 59 tissue paraffin­embedded blocks, which included 35 breast cancer tissues and 24 galactophore hyperplasia tissues. Western blot analysis was used to detect protein expression levels of ILP­2 in breast cancer cell lines such as HCC­1937, MX­1 and MCF­7 as well as breast gland cell line MCF 10A. ILP­2 was silenced by siRNA in HCC­1937, MX­1 and MCF­7 cell lines. MTT assays, scratch assays and AO­EB double staining analysis were conducted to evidence the role of ILP­2 on breast cancer cell growth. Results from this study showed increased ILP­2 expression in breast cancer tissues and breast cancer cell lines such as HCC­1937, MX­1 and MCF­7. Cell viability or rate of cell migration of HCC­1937, MX­1 and MCF­7 cell lines was significantly inhibited when ILP­2 was knocked down by siRNA. The apoptosis rate of HCC­1937, MX­1 and MCF­7 cell lines was increased when compared with that of the control group. Thus, ILP­2 plays an active role in the growth of breast cancer cells.

Nrf2: bane or blessing in cancer?

BACKGROUND: The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor-E2-related factor 2 (Nrf2)-antioxidant response element pathway serves a major function in endogenous cytoprotection in normal cells. Nrf2 is a transcription factor that mainly regulates the expression of a wide array of genes that produce the antioxidants and other proteins responsible for the detoxification of xenobiotics and reactive oxygen species. Nrf2 mediates the chemoprevention of cancer in normal cells. RESULTS AND DISCUSSION: Growing body of evidence suggests that Nrf2 is not only involved in the chemoprevention of normal cells but also promotes the growth of cancer cells. However, the mechanism underlying the function of Nrf2 in oncogenesis and tumor protection in cancer cells remains unclear and thus requires further study. CONCLUSION: This review aims to rationalize the existing functions of Nrf2 in chemoprevention and tumorigenesis, as well as the somatic mutations of Nrf2 and Keap1 in cancer and Nrf2 cross talk with miRNAs. This review also discusses the future challenges in Nrf2 research.

Inhibitor of apoptosis protein-like protein-2 as a novel serological biomarker for breast cancer.

Inhibitor of apoptosis protein-like protein-2 (ILP-2) has only been detected in the testis and in lymphoblastoid cells. Although previous studies have not reported the presence of ILP-2 in breast cancer tissues, this study indicates the presence of ILP-2 in breast cancer serum samples. To validate whether ILP-2 is a novel serological biomarker for breast cancer, we conducted two-dimensional gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry analysis on 400 breast cancer serum samples and 40 non-cancer serum samples (i.e., healthy controls). We then performed a Western blot analysis of 10 breast cancer serum samples and 10 non-cancer serum samples. Finally, we analyzed 35 serum samples from healthy controls or subjects with breast cancer, other types of cancer, galactophore hyperplasia or breast cancer post-surgery by using 2DE and enzyme-linked immunosorbent assay. Our results indicate that ILP-2 is a novel breast cancer biomarker in the peripheral blood.

Correlation of expression of human arrest-defective-1 (hARD1) protein with breast cancer.

Human arrest-defective-1 (hARD1) was reported to be important in regulating cell cycle and promoting lung cancer cell proliferation. Here we have investigated the correlation between hARD1 and breast cancer. Analysis with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM) demonstrated that overexpression of hARD1 was associated with increased proliferation of MCF-7 cell, a human breast cancer cell line. Western blotting and immunohistochemical staining assay showed that hARD1 presented higher in breast cancer tissue than the adjacent tissue; accumulation of hARD1 protein was higher in 86% (37/43) of breast cancer, far more than noncancer samples. Our results suggest that hARD1 might play an important role in breast cancer carcinogenesis.

[hARD1 antiserum preparation and primary immunohistochemical analysis of hARD1 in tumor tissues].

Human arrest defective 1 (hARD1) is an acetyltransferase; its physiological significance remains unclear. To explore the relationship between ARD1 protein and tumors, we detected the hARD1 protein in tumor tissues in vivo. We cloned hARD1 gene from Hela cell and construct recombinant plasmid pET28b-hARD1. The recombinant plasmid was transformed into E. coli BL21 (DE3)plysS. hARD1 protein was expressed by inducing with IPTG(1 mmol/L) and purified up to 95% through Ni2+ chelation affinity chromatography. We used the purified hARD1 protein as antigen immunized the Balb/c mice and obtained the hARD1 specific polyclonal antiserum. Through immunohistochemical analysis of different tumor tissues in vivo, we found that hARD1 expressed at high frequency in breast cancer, prostate cancer and lung cancer, especially, hARD1 expression frequency in breast cancer was up to 70%, which is higher than in the other tumors. These results indicate that the high expression level of hARD1 could be an indicator of the breast cancer. This new finding would be a foundation to further explore the relationship between breast tumor and hARD1.