Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways

Abstract

Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for therapy. Recently the possibilities of more specific, targeted therapies have sparked the interest of clinical and basic researchers as approaches to kill cancer cells. However, there are also problems associated with these targeted therapies. Two key signaling pathways involved in the regulation of cell growth are the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Dysregulated signaling through these pathways is often the result of genetic alterations in critical components in these pathways as well as mutations in upstream growth factor receptors. Furthermore, these pathways may be activated by chemotherapeutic drugs and ionizing radiation. This review documents how their abnormal expression can contribute to drug resistance as well as resistance to targeted therapy. This review will discuss in detail PTEN regulation as this is a critical tumor suppressor gene frequently dysregulated in human cancer which contributes to therapy resistance. Controlling the expression of these pathways could improve cancer therapy and ameliorate human health.

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy

“…[3][4][5][6] Shc recruits the growth factor receptor-bound protein 2 and the son of sevenless homolog protein, resulting in the loading of membrane-bound Ras with GTP. 15 Ras can also be activated by growth factor receptor tyrosine kinases (RTK), such as insulin-like growth factor-1 receptor, via intermediates like insulin receptor substrate proteins that bind growth factor receptor-bound protein 2.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12] Mutations can occur in the genes encoding pathway constituents (for example, Ras and Raf), upstream receptors (for example, Kit, Fms and Fms-like tyrosine kinase (Flt)-3) or chromosomal translocations (for example, BCR-ABL and TEL-platelet-derived growth factor receptor (PDGFR)), which activate this pathway. Chemotherapeutic drugs frequently used in leukemia therapy often activate this pathway.…”

“…1,2 This pathway relays this information through interactions with various other proteins to the nucleus to control gene expression. [1][2][3][4][5][6][7][8][9][10][11][12] This review will discuss how these pathways may be aberrantly regulated in leukemia and contribute to therapeutic sensitivity/resistance and in some cases poor prognosis. [4][5]13 Inhibition of Ras (or Ras-related molecules), Raf, MEK and ERK may prove useful in leukemia treatment.…”

Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells

“…[1][2][3][4][5] Among the signaling pathways downstream of the EGFR, the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways have been shown to regulate apoptosis and their deregulation is often implicated in malignant transformation. [5][6][7][8][9][10][11] The PI3K p110 catalytic subunit gene (PIK3CA) is one of the most frequently mutated genes in breast cancer. [12][13][14][15] Phosphatidylinositol (PI) (3,4)P 2 and PI(3,4,5)P 3 produced by class 1A PI3Ks recruit phosphoinositide dependent kinase-1 (PDK1) as well as Akt isoforms to the plasma membrane by interacting with their pleckstrin homology (PH) domains.…”

Reversal of multidrug resistance in MCF-7/Adr cells by codelivery of doxorubicin and BCL2 siRNA using a folic acid-conjugated polyethylenimine hydroxypropyl-β-cyclodextrin nanocarrier

“…Therefore, it is apparent that to efficiently suppress the overall resistance to chemotherapy, an important method to suppress therapeutic resistance is through the use of inhibitors that target the mechanism of resistance, such as inhibiting the expression of MDR1 or BCL2. 4 RNA interference (RNAi) has emerged as an attractive technology for silencing the expression of specific genes in human cells. 5 In the physiological RNAi pathway of gene silencing, double-stranded RNAs are processed into small interfering RNAs (siRNAs) by the RNase enzyme Dicer.…”