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Review

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

1
Faculty of Health Sciences, Curtin Medical School, Curtin University, Bentley 6102, Australia
2
Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley 6102, Australia
3
Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 08035 Barcelona, Spain
4
MD Anderson Cancer Center, Investigational Cancer Therapeutics Department, Houston, TX 77030, USA
5
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
6
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
*
Authors to whom correspondence should be addressed.
Authors contributed equally.
Academic Editor: Deepak Nagrath
Cancers 2021, 13(7), 1538; https://doi.org/10.3390/cancers13071538
Received: 2 February 2021 / Revised: 11 March 2021 / Accepted: 15 March 2021 / Published: 26 March 2021
(This article belongs to the Special Issue Cellular Plasticity and the Untapped Therapeutic Potential in Cancer)
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.
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. View Full-Text
Keywords: PI3K pathway; mechanisms of resistance; PI3K pathway inhibitors PI3K pathway; mechanisms of resistance; PI3K pathway inhibitors
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MDPI and ACS Style

Wright, S.C.E.; Vasilevski, N.; Serra, V.; Rodon, J.; Eichhorn, P.J.A. Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity. Cancers 2021, 13, 1538. https://doi.org/10.3390/cancers13071538

AMA Style

Wright SCE, Vasilevski N, Serra V, Rodon J, Eichhorn PJA. Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity. Cancers. 2021; 13(7):1538. https://doi.org/10.3390/cancers13071538

Chicago/Turabian Style

Wright, Sarah C.E., Natali Vasilevski, Violeta Serra, Jordi Rodon, and Pieter J.A. Eichhorn 2021. "Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity" Cancers 13, no. 7: 1538. https://doi.org/10.3390/cancers13071538

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