REVIEW article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
PI3K/Akt/mTOR signaling as a novel modulator of ABC transporters: Cutting-Edge Approaches to Mitigate Cancer Drug Resistance
Provisionally accepted
- 1Liaoning Cancer Hospital and Institute, Shenyang, China
- 22. Heping District Central Hospital Health Service Center, Shenyang, China
- 3Cancer Hospital of Dalian University of Technology (Liaoning Cancer Institute and Hospital), Shenyang, China
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Cancer drug resistance remains a formidable challenge that undermines the efficacy of chemotherapeutics and targeted therapies. Among the multifaceted mechanisms driving multidrug resistance (MDR), ATP-binding cassette (ABC) transporters play a central role by actively expelling cytotoxic agents, thereby reducing intracellular drug accumulation. Emerging evidence reveals that the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway acts as a pivotal regulator of ABC transporters, forming a dynamic molecular axis that enhances efflux activity, sustains cancer cell survival, and promotes therapeutic escape. Aberrant activation of this pathway upregulates key transporters, P-glycoprotein (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2), through transcriptional, translational, and post-translational mechanisms, thereby reinforcing MDR. Conversely, pharmacological or genetic inhibition of PI3K/Akt/mTOR signaling has been shown to suppress transporter expression and restore drug sensitivity. This review delineates the intricate crosstalk between PI3K/Akt/mTOR and ABC transporters across diverse malignancies, emphasizing recent advances in molecular inhibitors, natural compounds, and nanotechnology-based interventions that disrupt this resistance network. Understanding this signaling-transport interface offers promising avenues for developing synergistic therapies aimed at overcoming MDR and improving clinical outcomes in refractory cancers.
Keywords: ABC transporter, BCRP (ABCG2), drug resisitance, MRP1 (ABCC1), P-gp (P-glycoprotein), PI3K/AKT/ mTOR pathway
Received: 12 Nov 2025; Accepted: 12 Feb 2026.
Copyright: © 2026 Jia, Kong, Jin, Zhu and Bai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiangyu Zhu
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