mTOR Cross-Talk in Cancer and Potential for Combination Therapy

Abstract

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy.

Novel therapeutic roles of MC‐4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

“…An important and promising target for metastatic RCC to date is mTOR, which is a pivotal regulator of the metabolic pathway of a cell. mTOR receives input from sensors of energy, nutrients, and stress and produces output that regulates protein synthesis and cell growth . The activation of class I PI3K could lead to activation of Akt‐mTOR signaling pathway, which in turn inhibits autophagy .…”

“…Although several types of vascular endothelial growth factor‐ and mechanistic target of rapamycin (mTOR)‐targeted drugs have been approved as first‐line therapies for the treatment of metastatic RCC, more than 40% of patients do not respond to these agents . In particular, mTOR signaling pathway is a pivotal regulator of cellular growth, differentiation, survival, metabolism, and stress response . mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E‐BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis.…”

“…mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E‐BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis. mTORC2 phosphorylates serum/glucocorticoid regulated kinase 1 (SGK1), Akt, Ras‐related C3 botulinum toxin substrate 1 (Rac1), and protein kinase Cα (PKCα) to regulate cell survival, glycolytic enzymes, pentose phosphate pathway enzymes, glutaminase, and cytoskeletal organization . Due to feedback between mTORC1 and mTORC2, crosstalk with other pathways leading to the compensatory activation of extracellular signal‐regulated kinase (ERK)/mitogen‐activated protein kinase pathway (MAPK), and a higher risk of side effects, the therapeutic efficacy of FDA‐approved mTORC1 inhibitors such as everolimus is limited …”

“…3 In particular, mTOR signaling pathway is a pivotal regulator of cellular growth, differentiation, survival, metabolism, and stress response. [4][5][6][7] mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis. mTORC2 phosphorylates serum/glucocorticoid regulated kinase 1 (SGK1), Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), and protein kinase Cα (PKCα) to regulate cell survival, glycolytic enzymes, pentose phosphate pathway enzymes, glutaminase, and cytoskeletal organization.…”

Selective Inhibition of Kras Signaling by Combination of Low Dose Rapamycin and Paclitaxel in Vivo

“…По этой причине альтернативным направ-лением терапии опухолей, имеющих мутации в гене KRAS, становится применение таргетных препаратов, действие которых направлено на избирательное ингиби-рование отдельных компонентов MEK/ERK и PI3K/AKT сигнальных каскадов, участвующих в регуляции про-цессов пролиферации, дифференцировки и выживания клеток. Результаты клинических исследований, про-водившихся в этом направлении, показали, что ис-пользование ингибиторов mTOR (рапамицина (RAP) и его производных -рапалогов) оказывает противо-опухолевое действие на злокачественные новообразо-вания молочной железы, печени, нейроэндокринной и лимфатической систем [2,3]. Более того, в ряде экс-периментов показана способность RAP тормозить развитие индуцированных химическими канцерогенами опухолей у грызунов и снижать частоту возникновения спонтанных опухолей у мышей различных линий [4].…”