TY - JOUR
T1 - Mechanisms of resistance to pi3k inhibitors in cancer
T2 - Adaptive responses, drug tolerance and cellular plasticity
AU - Wright, Sarah Christine Elisabeth
AU - Vasilevski, Natali
AU - Serra, Violeta
AU - Rodon, Jordi
AU - Eichhorn, Pieter Johan Adam
N1 - Funding Information:
Funding: The work was funded by a start‐up grant provided by Curtin University.
Publisher Copyright:
© 2021 by the author. Licensee MDPI, Basel, Switzerland.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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 antitumour 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.
AB - 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 antitumour 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.
KW - Mechanisms of resistance
KW - PI3K pathway
KW - PI3K pathway inhibitors
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U2 - 10.3390/cancers13071538
DO - 10.3390/cancers13071538
M3 - Review article
C2 - 33810522
AN - SCOPUS:85102987674
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 7
M1 - 1538
ER -