Integrins in Cancer Drug Resistance: Molecular Mechanisms and Clinical Implications

Abstract

It is estimated that between 80 and 90% of mortality in cancer patients is directly or indirectly related to drug resistance. Consequently, overcoming drug resistance represents a significant challenge in the treatment of cancer. Integrins are transmembrane adhesion molecules that facilitate the linkage between the extracellular matrix (ECM) and the cytoskeleton, thereby enabling the activation of various cellular signaling pathways. Integrins are highly expressed in various cancers and contribute to cancer progression through invasion and metastasis. In addition, recent studies have revealed that integrins play a pivotal role in the development of drug resistance in cancer. This review will first provide an overview of integrin function and classification. It then discusses recent advances in understanding how integrins contribute to drug resistance in cancer, with a focus on ECM, drug transporters, the epithelial-to-mesenchymal transition (EMT), cancer stemness, PD-L1, and glycosylation. Finally, the potential applications of integrins as targets for therapeutic agents against drug-resistant cancers are also summarized.

Keywords: PD-L1; cancer; cancer stem cell (CSC); drug resistance; drug transporter; epithelial-to-mesenchymal transition (EMT); extracellular matrix (ECM); glycosylation; integrin; tyrosine kinase inhibitor (TKI).

Figure 1

Integrin activation, signaling, and function. Talin activation enables the specific binding of talin to the cytoplasmic tail of the β integrin subunit, which in turn separates the cytoplasmic tails of the αβ subunits, inducing a conformational change in the integrin from a bent conformation to a primed state. Kindlin also activates integrin by strengthening the association between talin and the β subunit tail. Subsequently, the integrin extends its conformation to become activated through binding to the extracellular matrix (ECM) and mechanical forces, thereby promoting integrin clustering and adhesion complex formation. The complex then upregulates various downstream signaling pathways, which ultimately lead to cellular functions.

Figure 2

Classification of integrins. Twenty-four integrins are composed of 18α and 8β subunits. They are classified into four major categories: collagen-binding integrins, laminin-binding integrins, LDV-binding integrins, and RGD-binding integrins. This classification is based on ligand binding specificity.

Figure 3

Cellular signalings and mechanisms of integrin-mediated drug resistance in cancer cells. Activated integrins promote multiple intracellular signaling pathways in cancer cells. Interaction of β1 integrin with annexin A6 secreted by cancer-associated fibroblasts (CAFs) stabilizes β1 integrin on the cell surface of cancer cells, which activates the FAK/YAP signaling pathway. Interaction of α-actinin 1 with β1 integrin activates β-catenin signaling through the β1 integrin-mediated FAK/PI3K/AKT pathway. Stanniocalcin 1 binds directly to β6 integrin to activate the αvβ6 integrin-mediated PI3K signaling pathway. The interaction of lipocalin 2 with β3 integrin results in increased αvβ3 integrin stability, which in turn triggers the activation of the Src/Akt/ERK signaling pathway. These signals then induce pro-survival and anti-apoptotic signals, resulting in the acquisition of drug resistance in cancer cells.

Figure 4

Molecular mechanisms of anticancer drug resistance mediated by integrins. (a) Integrins upregulate the expression of drug efflux transporters, including P-gp and MRP1, while simultaneously downregulating the expression of an equilibrative nucleoside transporter, ENT1, in tumor cells. This phenomenon contributes to the development of drug resistance. (b) Regulatory mechanisms underlying integrin signaling in tumor cells, which induces drug resistance, encompass integrin N-glycosylation, cross-linking of extracellular matrix (ECM) proteins, and ECM stiffness. (c) Epithelial-to-mesenchymal transition (EMT) also contributes to cancer drug resistance via induction of anti-apoptotic signaling and angiogenesis, acquisition of stemness, upregulation of immune checkpoint molecules, and increased immunosuppression.

Figure 5

Molecular mechanisms of anti-cancer therapy resistance mediated by integrins and PD-L1. (a) αvβ3 and αvβ6 integrins promote PD-L1 expression in tumor cells, thereby facilitating immune surveillance evasion and leading to anti-PD-1 immunotherapy resistance. (b) PD-L1 directly interacts with β6 integrin in tumor cells, thereby activating the αvβ6 integrin/FAK/STAT3 signaling pathway, which suppresses cisplatin-induced apoptosis. In addition, αvβ6 integrin activates TGF-β from a latent precursor to induce SOX4 expression, which contributes to anti-PD-1 immunotherapy resistance. (c) PD-L1 directly binds to β1 integrin, thereby activating NF-κB signaling and conferring resistance to cisplatin.