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.

Keywords: Cancer therapy; Combination inhibitor; PI3K/AKT/mTOR; RAF/MEK/ERK; Small molecular inhibitors.

Fig. 1

Schematic of the PI3K/AKT/mTOR and Raf/MEK/ERK signaling pathways. Growth factors, hormones, cytokines, GPCRs, and mitogens activate receptor tyrosine kinases (RTKs) recruiting PI3K to attach to the plasma membrane, where PI3K catalyzes PI (4,5) P2 to PI (3,4,5) P3. PTEN suppressed the process, and PTEN mutations could induce abnormal activation. PI (3,4,5) P3 promotes AKT activation via the activity of PDK1 and mTORC2. AKT activation induced cell cycle progression, cell growth, cell apoptosis, survival, glucose metabolism, protein synthesis, signal triggering and transduction, and phosphorylation of the downstream substrate TSC2. AKT activation suppressed the activity of TSC2 to promote the production of Rheb complex, resulting in mTORC1 activation. mTORC1 activation facilitates the initiation of eukaryotic protein translation. 4E-binding protein 1 (4E-BP1) activation enhanced the release of eukaryotic translation initiation factor 4E (eIF4E). RTK activation further accelerates guanine exchange factor to load RAS with GTP. RAS–GTP dimers recruit RAFs or RAF/MEK heterodimers to membranes, where tetramers consisting of RAF and MEK promote RAF activation. MEK activation is initiated by docking on RAF dimers, which further facilitate ERK phosphorylation. RTKs, receptor tyrosine kinase; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog; PDK1,3-pphosphoinositide-dependent kinase 1; mTOR, mechanistic target of rapamycin; TSC1, tuberous sclerosis 1; TSC2, tuberous sclerosis 2; 4E-BP, eIF4E-binding protein; GRB10, growth factor receptor-bound protein 10; IGF-1R, insulin-like growth factor 1 receptor; mLST8, mammalian lethal with SEC thirteen 8; RICTOR, rapamycin-insensitive companion of mTOR; S6K, ribosomal S6 kinase; FLCN, folliculin; ULK1, UNC-51-like kinase 1; RAPTOR, regulatory-associated protein of mTOR; RICTOR, rapamycin-insensitive companion of mTOR.

Fig. 2

Inhibitors of the PI3K/AKT/mTOR pathway. Various classes of agents target different effectors of the PI3K/AKT/mTOR pathway

Fig. 3

Comprehensive understanding and agent direction for targeting the RAF/MEK/ERK signaling pathway in cancer treatment