Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

Abstract

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3

“…Treatment with doxorubicin causes cellular damage through intercalating into DNA, preventing replication and subsequent ROS production during metabolism of the drug. 4,5,7,9 Cells transiently transfected with p53-responsive luciferase vectors were exposed to 100 nM doxorubicin for 24 h. Analysis of luciferase activity revealed that p53 became transcriptionally active in parental 22Rv-1 and LNCaP cells treated with doxorubicin, while most of this activity was abolished in the same cells transfected with p53DD (Fig. 1B).…”

“…The mechanism behind these increased or decreased changes in drug sensitivity is proposed to result from DNA damage-causing activation of p53, leading to a halt in cell cycle progression, induction of senescence and/or initiation of apoptosis. 4,7,40,49 Other researchers have found that augmentation of p53 activity in prostate cancer cell lines appear, to only promote cellular apoptosis a small percentage of the time when exposed to radiation. 46 The majority of the effects p53 activity has on the cell is to promote cellular senescence.…”

“…Since p53 is the "guardian of the genome," then successful treatment with these drugs would hinge on the presence of functional p53 within the cancer itself. 4,41,42 The genomic TP53 status of the 22Rv-1, LNCaP and DU145 prostate cancer cell lines have been reported ( Table 1). 43 Retroviral constructs expressing the full-length wild-type p53 protein (p53WT) and the truncated dominant-negative form of the p53 protein (p53DD) were stably introduced into the 22Rv-1 and LNCaP cell lines.…”

“…2 p53 is a sequence-specific transcription factor, the protein product of the TP53 gene (chromosome band 17p13.1), whose expression is increased in response to cellular stresses that cause DNA damage, such as UV radiation, cytotoxic drugs or hypoxia. [3][4][5] Furthermore, chemotherapeutic drug dosage may regulate the induction of quiescence or senescence as well as affect aging. [6][7][8][9] In a homeostatic state, cells produce and degrade low but equal concentrations of p53 protein, causing rapid turnover of the factor, the half-life being approximately 20 min.…”

Vascular-targeted agents for the treatment of angiosarcoma

“…In contrast to other kinase inhibitors MEK inhibitors, including selumetinib, do not compete with ATP binding to inhibit MEK phosphorylation, but rather interfere with MEK binding and the subsequent activation of downstream ERK [191]. Evidence of clinical efficacy for selumetinib monotherapy has been demonstrated in studies of patients with advanced colorectal cancer [192] and melanoma [193].…”