Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

Pottier, Charles; Fresnais, Margaux; Gilon, Marie; Jérusalem, Guy; Longuespée, Rémi; Sounni, Nor Eddine

doi:10.3390/cancers12030731

Cited by 350 publications

(265 citation statements)

References 92 publications

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“…Nevertheless, the efficacy of chemotherapy has been stagnant for many years. In contrast, the development of new and different therapies, such as targeted therapies for tyrosine kinases [2], as well as immunotherapy using immune-checkpoint inhibitors [3], has been an important leap in recent years. Either way, the ultimate goal is to kill tumor cells and protect normal cells.…”

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confidence: 99%

ESCRT-III-mediated membrane repair in cell death and tumor resistance

2020

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The plasma membrane is made of glycerophospholipids that separate the inner and outer parts of the cell. Under physiological conditions, it acts as a barrier and gatekeeper to protect cells from the environment. In pathological situations, it undergoes structural and functional changes, resulting in cell damage. Indeed, plasma membrane damage caused by various stresses (e.g., hypoxia, nutritional deficiencies, ultraviolet radiation, and chemotherapeutic agents) is one of the hallmarks of cell death. Phosphatidylserine exposure and plasma membrane blebbing usually occurs in apoptotic cells, while necrotic cells lose the integrity of the plasma membrane and thereby release intracellular damage-associated molecular patterns. In contrast, the endosomal sorting complex required for transport-III (ESCRT-III), an evolutionarily conserved protein complex with membrane fission machinery, plays a key role in the repair of damaged plasma membranes in various types of regulated cell death, such as necroptosis, pyroptosis, and ferroptosis. These emerging findings indicate that ESCRT-III is a potential target to overcome drug resistance during tumor therapy.

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confidence: 99%

ESCRT-III-mediated membrane repair in cell death and tumor resistance

2020

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“…Inhibitors emerged with more than one protein kinase as a target structure [9]. However, these inhibitors are also affected by resistance mechanisms [10].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

2020

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Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.

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“…Preclinical and early clinical studies with single-targeted agents have shown limited antitumor activity in ovarian cancer. Combining two or more therapeutic agents to target tumor cell survival pathways has become a new strategy to treat cancer [ 16 ]. In this study, we found that combined treatment of several FDA-approved targeted drugs—sunitinib, dasatinib, and everolimus—results in simultaneous inhibition of multiple signaling pathways and a better anti-tumor activity than any single treatment.…”

Section: Discussionmentioning

confidence: 99%

“…However, clinical trials with single-targeted agents have shown limited antitumor activity in ovarian cancer, which could be due to compensation by alternative growth/survival pathways. Thus, an emerging strategy for overcoming resistance is to combine inhibitors targeting multiple oncogenic pathways [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

Wen

Han

Dellinger

et al. 2020

Cancers

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More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone.

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Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

Cited by 350 publications

References 92 publications

ESCRT-III-mediated membrane repair in cell death and tumor resistance

ESCRT-III-mediated membrane repair in cell death and tumor resistance

Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

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