Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy

Abstract

The PI3K/AKT/mTOR and RAF/MEK/ERK pathways are commonly activated by mutations and chromosomal translocation in vital targets. The PI3K/AKT/mTOR signaling pathway is dysregulated in nearly all kinds of neoplasms, with the component in this pathway alternations. RAF/MEK/ERK signaling cascades are used to conduct signaling from the cell surface to the nucleus to mediate gene expression, cell cycle processes and apoptosis. RAS, B-Raf, PI3K, and PTEN are frequent upstream alternative sites. These mutations resulted in activated cell growth and downregulated cell apoptosis. The two pathways interact with each other to participate in tumorigenesis. PTEN alterations suppress RAF/MEK/ERK pathway activity via AKT phosphorylation and RAS inhibition. Several inhibitors targeting major components of these two pathways have been supported by the FDA. Dozens of agents in these two pathways have attracted great attention and have been assessed in clinical trials. The combination of small molecular inhibitors with traditional regimens has also been explored. Furthermore, dual inhibitors provide new insight into antitumor activity. This review will further comprehensively describe the genetic alterations in normal patients and tumor patients and discuss the role of targeted inhibitors in malignant neoplasm therapy. We hope this review will promote a comprehensive understanding of the role of the PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways in facilitating tumors and will help direct drug selection for tumor therapy.

Inhibitory Effect of Recombinant Tyrosine-sulfated Madanin-1, a Thrombin Inhibitor, on the behavior of MDA-MB-231 and SKOV3 Cells in vitro

“…Moreover, activated Akt and ERK are also implicated in orchestrating EMT by regulating EMT-inducing transcription factors 34,43 . Accordingly, research and clinical trials for anti-cancer agents targeting molecules in these pathways are being actively conducted 41,42,44 . Several agents are commonly used in clinical practice; alpelisib (PI3K p110α inhibitor) and everolimus (mTOR complex 1 inhibitor) have been approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer 45 .…”

Combination of Everolimus and Bortezomib Inhibits the Growth and Metastasis of Bone and Soft Tissue Sarcomas via JNK/p38/ERK MAPK and AKT Pathways

“…In addition, ERK activation can promote cell death by suppressing the AKT signaling pathway in renal cells [47]. Cross talk between ERK and AKT signaling pathways is reported in lung cancer [49][50][51] (Figure 7).…”

ZnO nanomaterials target mitochondrial apoptosis and mitochondrial autophagy pathways in cancer cells

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