Rictor-A Mediator of Progression and Metastasis in Lung Cancer

Abstract

Lung carcinoma is one of the most common cancer types for both men and women. Despite recent breakthroughs in targeted therapy and immunotherapy, it is characterized by a high metastatic rate, which can significantly affect quality of life and prognosis. Rictor (encoded by the RICTOR gene) is known as a scaffold protein for the multiprotein complex mTORC2. Among its diverse roles in regulating essential cellular functions, mTORC2 also facilitates epithelial-mesenchymal transition and metastasis formation. Amplification of the RICTOR gene and subsequent overexpression of the Rictor protein can result in the activation of mTORC2, which promotes cell survival and migration. Based on recent studies, RICTOR amplification or Rictor overexpression can serve as a marker for mTORC2 activation, which in turn provides a promising druggable target. Although selective inhibitors of Rictor and the Rictor-mTOR association are only in a preclinical phase, they seem to be potent novel approaches to reduce tumor cell migration and metastasis formation. Here, we summarize recent advances that support an important role for Rictor and mTORC2 as potential therapeutic targets in the treatment of lung cancer. This is a traditional (narrative) review based on Pubmed and Google Scholar searches for the following keywords: Rictor, RICTOR amplification, mTORC2, Rictor complexes, lung cancer, metastasis, progression, mTOR inhibitors.

Keywords: RICTOR amplification; Rictor overexpression; lung cancer; mTOR pathway; mTORC2.

Figure 1

Frequency of genetic alterations of the mTOR pathway in the most common histological subtypes of lung cancer. RICTOR amplification is the most common targetable genetic alteration in SCLC, and it is also one of the most frequent genetic alterations in lung ADC and SCC. RICTOR is highlighted with red color. For ADC and SCC, data (mutations and copy number alterations) were obtained from The Cancer Genom Atlas (Firehose Legacy) via www.cbioportal.org (downloaded on 20 December 2023). Only the alterations marked as putative drivers are shown in the picture. SCLC data were obtained from various studies [9,11,12,13,14,15], a subset of which [11,12,13,14] was also downloaded from www.cbioportal.org (downloaded on 20 December 2023). List of abbreviations: ADC, adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung carcinoma.

Figure 2

Cellular functions regulated by mTORC2 and related signaling pathways. Recent studies suggest that mTORC2 can be activated by receptor tyrosine kinases through PI3K signaling, AMP-activated protein kinase, or small GTPases. Once activated, mTORC2’s main targets include Akt, SGK 1, and PKC. By activating its targets, mTORC2 can regulate bioenergetic processes and actin cytoskeleton reorganization, thereby promoting survival and migration of the tumor cells. List of abbreviations: Akt, protein kinase B; AMPK, AMP-activated protein kinase; BAD, BCL2 associated agonist of cell death; DEPTOR, domain-containing mTOR-interacting protein; FoxO, forkhead box protein O1; GS, glycogen synthase; GSK3, glycogen synthase kinase-3; mLST8, mammalian lethal with SEC13 protein 8; mSin1, mammalian stress-activated map kinase-interacting protein 1; mTOR, mammalian target of rapamycin; mTORC2, mTOR complex 2; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; Protor1/2, protein observed with Rictor 1/2; Rictor, rapamycin-insensitive companion of mTOR; RTK, receptor tyrosine kinase; SGK1, serum glucocorticoid-regulated kinase 1.

Figure 3

The role of Rictor in the TGFβ-mediated epithelial–mesenchymal transition and metastasis formation. TGFβ1 is an important regulator of epithelial–mesenchymal transition and thus metastasis formation. In addition to Rho-A and Smad proteins, it can interact with PI3K, which activates mTORC2 and leads to the subsequent phosphorylation of Akt on Ser473 and initiation of downstream effector processes. Akt can also be phosphorylated by another protein complex containing Rictor and ILK. The activity of ILK is also required for the phosphorylation of Rictor in Thr1135, which can regulate the assembly of mTORC2. Once activated by either mTORC2 or the ILK/Rictor complex, Akt regulates cellular functions that can promote epithelial–mesenchymal transition and metastasis formation. List of abbreviations: Akt, protein kinase B; EMT, epithelial–mesenchymal transition; ILK, integrin-linked kinase; mTORC2, mTOR complex 2; PI3K, phosphatidylinositol 3-kinase; Rho-A, Ras homolog family member A; Rictor, rapamycin-insensitive companion of mTOR; SMAD, suppressor of mothers against decapentaplegic; TGFβ1, transforming growth factor β1.

Figure 4

Members of the mTOR pathway and their inhibitors. Several inhibitors of the mTOR pathway have been developed in recent years, and most of them are currently studied in clinical trials. Red color indicates inhibitors, which are currently studied in clinical trials, while blue color indicates inhibitors in the preclinical phase. List of abbreviations: Akt, protein kinase B; ILK, integrin-linked kinase; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PI3K, phosphatidylinositol 3-kinase; Rictor, rapamycin-insensitive companion of mTOR.