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Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies

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Abstract

Targeted therapy is a hallmark of cancer treatment that has changed the landscape of cancer management and enabled a personalized treatment approach. Nevertheless, the development of cancer resistance is a major challenge that is currently threatening the effective utilization of targeted therapies. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and tumorigenic potential. MET is a well-known driver of cancer resistance. A growing body of evidence revealed a major role of MET in mediating acquired resistance to several classes of targeted therapies. Deregulations of MET commonly associated with the development of cancer resistance include gene amplification, overexpression, autocrine activation, and crosstalk with other signaling pathways. Small-molecule tyrosine kinase inhibitors of MET are currently approved for the treatment of different solid cancers. This review summarizes the current evidence regarding MET-mediated cancer resistance toward targeted therapies. The molecular mechanisms associated with resistance are described along with findings from preclinical and clinical studies on using MET inhibitors to restore the anticancer activity of targeted therapies for the treatment of solid tumors.

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Abbreviations

EGFR:

Epidermal growth factor receptor

FGFR:

Fibroblast growth factor receptor

GAB1:

GRB2-associated binding protein 1

GRB2:

Growth factor receptor-bound protein 2

HCC:

Hepatocellular carcinoma

HER2:

Human epidermal growth factor receptor 2

HGF:

Hepatocyte growth factor

IPT:

Immunoglobulin-like regions in plexins and transcription factors

mAb:

Monoclonal antibody

MET:

Hepatocyte growth factor receptor

mTOR:

Mammalian target of rapamycin

ORR:

Overall response rate

OS:

Overall survival

PARP:

Poly (ADP-ribose) polymerase

PFS:

Progression-free survival

PI3K:

Phosphatidylinositol 3-kinase

PSI:

Plexin–semaphorin–integrin

RCC:

Renal cell carcinoma

RON:

Recepteur d’origine nantais

RTKs:

Receptor tyrosine kinases

S:

Serine

SEMA:

Semaphorin

STAT:

Signal transducer and activator of transcription

TKIs:

Tyrosine kinase inhibitors

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

Y:

Tyrosine

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  1. Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), P.O. Box 3030, Irbid, 22110, Jordan

    Nehad M. Ayoub, Dalia R. Ibrahim & Amer E. Alkhalifa

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  1. Nehad M. Ayoub
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  2. Dalia R. Ibrahim
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  3. Amer E. Alkhalifa
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Correspondence to Nehad M. Ayoub.

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Ayoub, N.M., Ibrahim, D.R. & Alkhalifa, A.E. Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies. Med Oncol 38, 143 (2021). https://doi.org/10.1007/s12032-021-01596-6

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