mTOR hyperactivity and RICTOR amplification as targets for personalized treatments in malignancies.

The increasing knowledge of molecular alterations in malignancies, including mutations and regulatory failures in the mTOR (mechanistic target of rapamycin) signaling pathway, highlights the importance of mTOR hyperactivity as a validated target in common and rare malignancies. This review summarises recent findings on the characterization and prognostic role of mTOR kinase complexes (mTORC1 and mTORC2) activity regarding differences in their function, structure, regulatory mechanisms, and inhibitor sensitivity. We have recently identified new tumor types with RICTOR (rapamycin-insensitive companion of mTOR) amplification and associated mTORC2 hyperactivity as useful potential targets for developing targeted therapies in lung cancer and other newly described malignancies. The activity of mTOR complexes is recommended to be assessed and considered in cancers before mTOR inhibitor therapy, as current first-generation mTOR inhibitors (rapamycin and analogs) can be ineffective in the presence of mTORC2 hyperactivity. We have introduced and proposed a marker panel to determine tissue characteristics of mTOR activity in biopsy specimens, patient materials, and cell lines. Ongoing phase trials of new inhibitors and combination therapies are promising in advanced-stage patients selected by genetic alterations, molecular markers, and/or protein expression changes in the mTOR signaling pathway. Hopefully, the summarized results, our findings, and the suggested characterization of mTOR activity will support therapeutic decisions.

Rictor-A Mediator of Progression and Metastasis in Lung Cancer.

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.

[he importance of mTOR hyperactivity and RICTOR amplification, and the associated targeted therapy possibilities in malignant tumours]. / Az mTOR-hiperaktivitás és a RICTORamplifikáció jelentosége, és az ezzel összefüggo célzott terápiás lehetoségek rosszindulatú daganatokban.

Failures of anti-tumour therapies and drug resistance initiate difficulties in cancer treatments often caused by alterations in signalling network activity, including PI3K/Akt/mTOR hyperactivity due to oncogenic mutations. In this review, we summarise the relevance of mTOR (mechanistic target of rapamycin) dysregulation identified decades ago, which is now known to be characteristic of many tumours. In this context, we present differences in activity, function and testability of mTOR kinase complexes (mTORC1 and mTORC2) differing in structure, regulatory mechanisms and inhibitor sensitivity. We highlight that genetic alterations, including RICTOR amplification and associated mTOR hyperactivity, are relevant in targeted therapy development. It is recommended to investigate mTOR profile activity in patients for whom mTOR inhibitor therapies are considered since the current first-generation mTOR inhibitors (rapamycin and analogues) may be ineffective in case of mTORC2 hyperactivity. Ongoing phase trials of new inhibitors and combination therapies are promising in advanced stage patients selected by molecular markers.

[Effects of 3D tissue structure on drug sensitivity - 3D bioprinted tissue mimetic structures in cancer research]. / 3D szöveti szerkezet hatása a gyógyszerérzékenységre ­ 3D bionyomtatott "szövetmodellek" a daganatkutatásban.

The issues surrounding the cost effectiveness of drug development and the ethical concerns associated with animal testing, emphasise the necessity for innovative in vitro models that allow enhanced pre-selection. Therefore, we aim to create 3D bioprinted tissue mimetic structures (TMS) utilizing various human cancer cell lines. We have generated TMSs from human tumour cell lines (breast, kidney, glioma), with detailed characterisation of the ZR75.1 cell line. In this study, the tissue heterogeneity, the growth rate, and the drug sensitivity of different in vitro and in vivo models were compared. Tissue formation occurs within the TMS after one week, with a tissue heterogeneity similar to in vivo growing tumours. Moreover, TMSs exhibit similar drug sensitivity to that observed in vivo. In summary, the established 3D bioprinted TMSs represent an advanced in vitro model, which can contribute to achieve a more effective and ethical drug development process in the field of oncology.