Gene expression (quantitative assessment) of genes that regulate the response of cancer cells to chemotherapy drugs
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. The function of the ERCC1 protein is predominantly in nucleotide excision repair (NER) of damaged DNA. Mutations in the human ERCC1 gene result that alter expression of this gene may play a role in carcinogenesis . Measuring ERCC1 activity may have utility in clinical cancer medicine because one mechanism of resistance to platinum chemotherapy drugs correlates with high ERCC1 activity. The ERCC1 (excision repair cross-complementation group 1) expression can predict response and survival rates in patients with NSCLC as well as colorectal cancer. In Non-small cell lung carcinoma (NSCLC), surgically removed tumors that receive no further therapy have a better survival if they are ERCC1-positive than if they are ERCC1-negative. Thus ERCC1 positivity is a favorable prognostic marker, referring to how the disease will proceed if not further treated. ERCC1-positive tumors do not benefit from adjuvant platinum chemotherapy. High ERCC1 is thus a negative predictive marker, referring to how it will respond to a specific type of treatment. By evaluating the expression levels of (ERCC1), we identify patients that may benefit from platinum-based chemotherapy - currently considered the standard of care in advanced NSCLC. Specifically, low expression levels of ERCC1 have been related to a better response and survival benefit from adjuvant cisplatin-based chemotherapy.
BRCA1 is a multifunctional protein that has been implicated in many normal cellular functions such as DNA repair, transcriptional regulation, cell-cycle checkpoint control and ubiquitination. Consequently, the presence or absence of functional BRCA1 has a significant effect on cellular response to chemotherapy. It was initially reported that overexpression of BRCA1 in human breast cancer cell lines resulted in increased resistance to cisplatin. Furthermore, antisense inhibition of endogenous BRCA1 expression promoted increased sensitivity to cisplatin that was associated with decreased DNA repair by NER and increased apoptosis.
The product of thymidylate synthase (TYMS) gene catalyzes the methylation of deoxyuridylate to deoxythymidylate and is critical for DNA replication and repair. The enzyme has been of interest as a target for cancer chemotherapeutic agents. It is considered to be the primary site of action for 5-fluorouracil, 5-fluoro-2-prime-deoxyuridine, and some folate analogs. Low expression levels of TYMS have been related to a better response and survival benefit from 5 FU/capecitabine/pemetrexed based chemotherapy.
The gene for ribonucleotide reductase M2 (RRM2) encodes for one of two non-identical subunits for ribonucleotide reductase. This reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides. Synthesis of the encoded protein (M2) is regulated in a cell-cycle dependent fashion. The expression of this gene has been associated with response to gemcitabine chemotherapy. High expression of RRM2 is associated with lack of response to gemcitabine.
The interferon-induced protein with tetratricopeptide repeats (IFIT3) is an interferone-induced gene, with unknown function to date. Its expression has been associated with response to paclitaxel.
The armadillo repeat containing, X-linked 3 (ARMCX3) gene encodes a protein of the ALEX family, which may play a role in tumor suppression. Its expression has been associated with response to cisplatin.
The tumor necrosis factor (ligand) superfamily, member 13 (TNFSF13B) gene encodes a cytokine that belongs to the tumor necrosis factor ligand family and acts as a potent B-cell activator in proliferation and differentiation. Its expression has been associated with response to paclitaxel.
The product of myosin VC (MYO5C) gene is likely to act on actin-based membrane trafficking. Its expression has been associated with response to cisplatin.
The gene encoding HtrA serine peptidase 1 (HTRA1), a member of the trypsin family of serine proteases, a possible regulator of the insulin-like growth factors that have been suggested as being associated with ovarian carcinogenesis and progression. It has also been suggested as a candidate tumor suppressor gene involved in promoting serine protease–mediated cell death. Its expression has been associated with response to cisplatin.
Topoisomerase-1 (TOPO-1) is an enzyme that alters the supercoiling of double stranded DNA. Higher expression of TOPO-1 has been associated with response to first-line chemotherapy containing irinotecan, a TOPO-1 inhibitor.
Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-binding cassette (ABC) polytopic membrane transporter of considerable clinical importance that confers multidrug resistance on tumor cells by reducing drug accumulation by active efflux. MRP1 was found to confer lack of response to anthracyclins, vinca alcaloids, epipodophylotoxins
The product of P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. P-glycoprotein has a wide tissue distribution and was the first ABC transporter identified to be overexpressed in breast cancer cell lines displaying multidrug resistance. PGP is a broad spectrum multidrug efflux pump that has 12 transmembrane domains and two ATP-binding sites. It is involved in the transport of neutral and cationic hydrophobic compounds (vinblastine, vincristine, doxorubicin, daunorubicin, etoposide and paclitaxel) out of cells. Overexpression of PGP is a negative predictive factor for several drugs sush as anthracyclins, paclitaxel, vinblastine.
The breast cancer resistance protein (BCRP) is expressed in a variety of tumours and is associated with resistance to a wide range of different anticancer agents including mitoxantrone, camptothecins, anthracyclines, flavopiridol and antifolates. Stem cells and tumour cells in a hypoxic environment may be protected from chemotherapeutic agents due to an increased expression of BCRP induced by hypoxia.
The O6-methylguanine-DNA methyltransferase (MGMT) gene, a key gene to DNA repair, plays a critical role in the development of cancer. Low MGMT expression and hypermethylation of the promoter of the MGMT gene has been correlated with response to Temozolomide (brand names Temodar and Temodal and Temcad) and better prognosis for glioblastomas.