Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity
| Autor: | Pieter Johan Adam Eichhorn, Sarah Christine Elisabeth Wright, Violeta Serra, Jordi Rodon, Natali Vasilevski |
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| Přispěvatelé: | Institut Català de la Salut, [Wright SCE, Vasilevski N] Faculty of Health Sciences, Curtin Medical School, Curtin University, Bentley 6102, Australia. Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley 6102, Australia. [Serra V] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Rodon J] MD Anderson Cancer Center, Investigational Cancer Therapeutics Department, Houston, TX 77030, USA. [Eichhorn PJA] Faculty of Health Sciences, Curtin Medical School, Curtin University, Bentley 6102, Australia. Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley 6102, Australia. Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance Neoplasm [PHENOMENA AND PROCESSES] Angiogenesis Motility Review Biology lcsh:RC254-282 neoplasias [ENFERMEDADES] 03 medical and health sciences 0302 clinical medicine PI3K pathway inhibitors Drug tolerance medicine PI3K/AKT/mTOR pathway Otros calificadores::/terapia [Otros calificadores] Resistència als medicaments fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS] Hyperactivation Cell growth Càncer - Tractament Cancer Other subheadings::/therapy [Other subheadings] lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease PI3K pathway Neoplasms [DISEASES] 030104 developmental biology Oncology Cellular plasticity mechanisms of resistance 030220 oncology & carcinogenesis Neuroscience |
| Zdroj: | Scientia Cancers, Vol 13, Iss 1538, p 1538 (2021) Cancers |
| Popis: | Simple Summary The phosphoinositide-3-kinase (PI3K) pathway is the most frequently activated pathway in human cancers. Consequently, a number of compounds targeting the various nodes of this pathway have been developed. However, the majority of these compounds have been unsuccessful in patients due to high levels of toxicity, as well as their inability to effectively downregulate the pathway to levels required for tumour responses. This inability to downregulate the pathway is partially mediated by intrinsic adaptive response, also known as compensatory mechanisms or feedback loops, which reactivate the pathway following inhibition; limiting the effectiveness of these compounds. In this review we highlight the mechanisms of action of these adaptive responses and highlight potential combinatorial strategies to delay tumour progression. Abstract The phosphatidylinositol-3-kinase (PI3K) pathway plays a central role in the regulation of several signalling cascades which regulate biological processes such as cellular growth, survival, proliferation, motility and angiogenesis. The hyperactivation of this pathway is linked to tumour progression and is one of the most common events in human cancers. Additionally, aberrant activation of the PI3K pathway has been demonstrated to limit the effectiveness of a number of anti-tumour agents paving the way for the development and implementation of PI3K inhibitors in the clinic. However, the overall effectiveness of these compounds has been greatly limited by inadequate target engagement due to reactivation of the pathway by compensatory mechanisms. Herein, we review the common adaptive responses that lead to reactivation of the PI3K pathway, therapy resistance and potential strategies to overcome these mechanisms of resistance. Furthermore, we highlight the potential role in changes in cellular plasticity and PI3K inhibitor resistance. |
| Databáze: | OpenAIRE |
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