mTOR pathway in colorectal cancer: an update

Abstract

The mammalian target of rapamycin (mTOR) has emerged as a potential target for drug development, particularly due to the fact that it plays such a crucial role in cancer biology. In addition, next-generation mTOR inhibitors have become available, marking an exciting new phase in mTOR-based therapy. However, the verdict on their therapeutic efectiveness remains unclear. Here we review phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling as one of the primary mechanisms for sustaining tumor outgrowth and metastasis, recent advances in the development of mTOR inhibitors, and current studies addressing mTOR activation/inhibition in colorectal cancer (CRC). We will also discuss our recent comparative study of diferent mTOR inhibitors in a population of colon cancer stem cells (CSCs), and current major challenges for achieving individualized drug therapy using kinase inhibitors.

The tumor-suppressor gene LZTS1 suppresses colorectal cancer proliferation through inhibition of the AKT–mTOR signaling pathway

“…mTOR plays an essential role in downstream signaling of the AKT pathway and is involved in diverse cellular processes including proliferation, differentiation and apoptosis, mainly via deregulated signal transduction and the subsequent hyper-activation of the critical effectors S6K1 and EIF4E [26,27]. Moreover, the AKT-mTOR pathway is frequently activated and plays a critical role in tumor growth and metastasis in various cancers, including CRC [27,28]. Thus, we hypothesize that LZTS1 affects CRC cell proliferation and tumor growth by controlling the AKT/mTOR signaling pathway.…”

Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells

“…PI3K signaling is further known to confer survival of a wide variety of cells including cancer cells [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55] and neurons [56,57,58,59]. Chorein is particularly important for function and viability of neurons and skeletal muscle cells [6,11].…”

2165 Combination of cetuximab and PP242 synergistically suppress the progression of wild-type KRAS colorectal carcinoma

“…14 Moreover, it was interesting to observe the inhibition of CSC growth with the next-generation mTOR inhibitor 13,14 or CTX alone, 21 but it is still unknown whether there is a synergic effect against CSCs when mTOR and EGFR are co-inhibited. Given the importance of mTOR pathway in the progression and recurrence of colorectal carcinoma, and the positive-feedback loops to EGFR following therapy with next-generation mTOR inhibitor, a combination of CTX and PP242 was a reasonable strategy which might bring benefit to mCRC patients.…”

“…The increased mTOR complex 2 activity and the suppression of the negative-feedback loop to IR/IRS and PI3K following mTORC1 targeting were the major reasons for failure of mTORC1 inhibitors. 13 After that, the emergence of next-generation mTOR inhibitors achieved exciting treatment efficacy against colorectal carcinomas in vitro, and it was interesting to observe the inhibited growth of colorectal cancer stem-like cells (CSCs) by the treatment of PP242 from the previous studies.…”