Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response.

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). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

“…35 In agreement, miR-373 overexpression reduced Akt phosphorylation without affecting the overall amount of Akt (Figure 6e). Figure 5e.…”

“…Cells were harvested and subjected to western blot analysis of total Akt1, phosphorylated Akt (pAkt) and GAPDH, n = 2 Activation of the PI3K/Akt pathway confers chemotherapy resistance. 35 Therefore, inhibition of PIK3CA may contribute to the enhanced death of A549 cells upon combined treatment with miR-373 and cisplatin.…”

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

“…Furthermore, PI3K activation via activating mutations of RAS contributes to RASmediated cellular transformation (9,10). In addition to promoting cancer cell proliferation and survival, activation of the PI3K pathway mediates resistance to both RTK inhibitors and genotoxic agents (11,12), such that PI3K inhibition increases cancer cell sensitivity to targeted agents, as well as platinum-based drugs and taxanes (13)(14)(15). Selective inhibition of key nodes of the PI3K pathway represents an attractive therapeutic intervention for the treatment of solid and hematologic cancers, and both pan-class I and isoform-selective PI3K inhibitors have entered clinical testing (3,16).…”

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

“…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.…”