The CDK inhibitors in cancer research and therapy

Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in different human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the specific purpose of their research. For this purpose, the targets, commercial availability and IC50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitor

Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing ErbB-2

INTRODUCTION: Akt1, Akt2 and Akt3 kinases are downstream components of phosphoinositol 3-kinase derived signals from receptor tyrosine kinases, which influence cell growth, proliferation and survival. Akt2 overexpression and amplification have been described in breast, ovarian and pancreatic cancers. The present study was designed to investigate the prognostic significance of activated Akt in primary breast cancer and its association with other tumour biomarkers. METHODS: Using a two-site chemiluminescence-linked immunosorbent assay, we measured the quantitative expression levels of total phosphorylated (P-S473) Akt (Akt1/Akt2/Akt3) on cytosol fractions obtained from fresh frozen tissue samples of 156 primary breast cancer patients. RESULTS: Akt phosphorylation was not associated with nodal status or ErbB-2 protein expression levels. High levels of phosphorylated Akt correlated (P < 0.01) with poor prognosis, and the significance of this correlation increased (P < 0.001) in the subset of patients with ErbB-2 overexpressing tumours. In addition, phosphorylated Akt was found to be associated with mRNA expression levels of several proliferation markers (e.g. thymidylate synthase), measured using quantitative real-time RT-PCR. CONCLUSION: Our findings demonstrate that, in breast cancer patients, Akt activation is associated with tumour proliferation and poor prognosis, particularly in the subset of patients with ErbB2-overexpressing tumours

ErbB2 signaling in breast cancer : the role of ErbB, Akt and ShcA phosphorylation

Breast cancer is the most common malignancy in women and is estimated to account for more than 200,000 new cancer cases in the United States in the year 2002. It now represents the second leading cause of death (40,000) from cancer in women. Although the number of new breast cancer cases has been increasing, the death rate has been steadily decreasing. This trend may be due to earlier diagnosis, and/or increased survival resulting from the use of adjuvant therapy. Clinical outcome is affected by prognostic predictive factors. Prognostic factors are associated with either the metastatic or the growth potential of the primary tumor, while predictive factors are associated with the relative sensitivity and/or resistance to specific therapies. Routinely available prognostic indicators include tumor size, type, and grade, axillary lymph node status, estrogen and progesterone receptor status. Estrogen receptor status and progesterone receptor status also serve as predictive factors for expected response to hormone therapy. Many other molecular markers are being investigated for their clinical usefulness. One of the major molecular prognostic and predictive markers in breast cancer is the amplification status of the proto-oncogene ErbB2 (HER-2/ neu). The ErbB2 proto-oncogene is a component of a four-member family of closely related growth factor receptors that includes the epidermal growth factor receptor (ErbB1/HER1), ErbB3 (HER3), and ErbB4 (HER4). The human gene is located on chromosome 17q21 and encodes a 185-kDa protein with tyrosine kinase activity that is also known by the designation p185. Structurally, the protein has extracellular, transmembrane, and a cytoplasmic domain, the latter of which contains the tyrosine kinase domain and shares significant homology, although is distinct, from EGFR. Under normal circumstances, low levels of ErbB2 expression are detectable immunohistochemically in a variety of fetal and adult epithelial cells throughout the gastrointestinal, respiratory, and genitourinary tracts. Amplification of the ErbB2 protooncogene or overexpression of the p185 protein, which generally correlate with each other, has been identified in 10% to 34% of breast cancers as well as in gastrointestinal, pulmonary, and genitourinary tumors. The mechanism by which overexpressed ErbB2 leads to a neoplastic phenotype occurs by activation of several different signaling pathways that lead to gene activation, ultimately resulting in cell proliferation. Although the mechanism of activation of ErbB2 has not been completely elucidated, it is thought to involve the formation of heterodimers with other members of the epidermal growth factor family of receptors or spontaneous homodimerization. This study was designed to compare the prognostic value of phosphorylated ErbB2 in well characterized primary breast cancer samples. Seventy primary breast cancers with a median of 45 months of follow-up were analyzed for quantitative levels of phosphorylated ErbB2 using new sensitive chemiluminescence-linked immunoassay (CLISA). Phosphorylated ErbB2 data were compared with clinical, histological and outcome variables as well as quantitative mRNA and protein expression levels of ErbB family members. ErbB2 – overexpressing tumors contained significantly more phosphorylated ErbB2, however PY1248 could be detected in some of low ErbB2 expression tumors. ErbB2 phosphorylation was correlated with disease free and overall survival and reduced estrogen receptor and progesterone receptor contents. Comparison of ErbB family expression on mRNA level with ErbB2 phosphorylation revealed significant correlation with ErbB2 and EGFR but inverse correlation with ErbB3 and ErbB4. Similar correlations were found also with respect to protein expression levels of these factors. We have also investigated total (pan) tyrosine, serine and threonine phosphorylated ErbB2 in 153 breast cancer samples by two-site CLISA assays. Serine and threonine phosphorylated ErbB2 could be detected only in low ErbB2 – expressing tumors, no serine and threonine phosphorylation was detectable in ErbB2 overexpressing tumors. As in case of PY1248, ErbB2 – overexpressing tumors contained significantly more tyrosine phosphorylated ErbB2, but ErbB2 tyrosine phosphorylation was detectable in some of low ErbB2 expression tumors as well. Due to the fact that tumors we selected for this study were mostly aggressive tumors, it was impossible to analyze the prognostic value of ErbB2 phosphorylations. Akt1, Akt2 and Akt3 kinases are involved in the signal transduction pathway downstream of receptor tyrosine kinases via phosphoinosytol-3-kinase, influencing cell growth, proliferation and survival. Akt2 overexpression and amplification have been described in breast, ovarian and pancreatic cancers. In this study we measured the quantitative expression levels of total phosphorylated (P-S473) Akt (Akt1/2/3) by means of a two-site CLISA on cytosol extracts obtained from 156 primary breast cancer tissue samples. We aimed to clarify the prognostic significance of activated Akt in primary breast cancer in association with other tumor biomarkers. Akt phosphorylation was not associated with the nodal status and the ErbB2 expression. Only very high expression levels of P-Akt correlated with poor prognosis. More importantly, the prognostic value of P-Akt expression increased in ErbB2 overexpressing subset of patients. In addition, P-Akt was found to be associated with mRNA expression levels of several proliferation markers, such as thymidylate synthase, thymidine kinase 1, survivin, topoisomerase II alpha and transcription factor E2F, measured by quantitative real-time PCR (Q-RT-PCR). Shc adapter/docking proteins are an important component of receptor tyrosine kinase signaling pathways because they are involved in transducing the activation signals from receptor or cytoplasmic tyrosine kinases to downstream signaling cascades. At least three genes, shcA, shcB, and shcC, are known to encode Shc proteins. ShcA has been found to be phosphorylated rapidly and efficiently by all tyrosine kinases tested to date. These phosphorylation sites have been mapped to Y339, Y240, and Y317. In addition to tyrosine phosphorylation, ShcA can also be phosphorylated at serine/threonine residues. We have investigated pan- tyrosine, serine and threonine phosphorylated ShcA in 153 breast cancer samples by two-site CLISA assays. P-ShcA was found to be weekly associated with PT ErbB2 levels and weekly inversely correlated with P-Akt levels. A very good correlation was found between PS ShcA and PY SchA. Since it was the same collective of tumors, as the one used for ErbB2 pan-S, T and Y phosphorylation assessment, it was also impossible to analyze the prognostic value of phospho-SchA

Anti-Cancer Drugs Targeting Protein Kinases Approved by FDA in 2020

Cancers are a large group of diseases that mostly emerge because of the uncontrollable action of many different genes in human cells [...

Kinases and Cancer

Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...]

Increased Level of Phosphorylated ShcA Measured by Chemiluminescence-Linked Immunoassay Is a Predictor of Good Prognosis in Primary Breast Cancer Expressing Low Levels of Estrogen Receptor

The SH2 domain-containing adaptor protein ShcA is a proto-oncogene involved in growth factor receptor signaling. The role of phosphorylated ShcA is to link receptor tyrosine kinases with the SH2-containing adaptor protein Grb2, thus facilitating signal transduction from receptor tyrosine kinases to Ras, leading to MAPK activation. The present study was designed to investigate the prognostic significance of phosphorylated ShcA in primary breast cancer and its association in the interactions between the ER and ErbB2 pathways. Using a two-site chemiluminescence-linked immunosorbent assay, we detected the quantitative expression levels of total tyrosine- and threonine-phosphorylated ShcA in cytosol fractions obtained from fresh frozen tissue samples of 153 selected primary breast cancer patients. ShcA phosphorylation was not associated with nodal status, estrogen receptor (ER) status or grading. High levels of both tyrosine (pYShcA) and serine (pSShcA) phosphorylated ShcA correlated with good prognosis (p &lt; 0.01), with respect to both disease-free (DFS) and overall survival (OS). In addition, pShcA levels were found to correlate with threonine-phosphorylated ErbB2 and inversely with phosphorylated Akt (pAkt), as well as ErbB2 and ER expression levels. Our findings demonstrate that ShcA activation in primary breast cancer patients correlates with low levels of ER, and is associated with good prognosis