Improving Outcomes of Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma: New Data and Ongoing Trials

Abstract

Targeted therapies such as oral tyrosine kinase inhibitors (TKIs) are the main therapeutic strategy effective for advanced hepatocellular carcinoma (HCC). Currently six tyrosine kinase inhibitors for HCC therapy have been approved. The newly approved first-line drug donafenib represent the major milestones in HCC therapeutics in recent years. However, drug resistance in HCC remains challenging due to random mutations in target receptors as well as downstream pathways. TKIs-based combinatorial therapies with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies afford a promising strategy to further clinical application. Recent developments of nanoparticle-based TKI delivery techniques improve drug absorption and bioavailability, enhance efficient targeting delivery, prolonged circulation time, and reduce harmful side effects on normal tissues, which may improve the therapeutic efficacy of the TKIs. In this review, we summarize the milestones and recent progress in clinical trials of TKIs for HCC therapy. We also provide an overview of the novel nanoparticle-based TKI delivery techniques that enable efficient therapy.

Sporadic Medullary Thyroid Carcinoma: Towards a Precision Medicine

“…Mutations or overexpression of TKRs are frequently detected in cancer cells ( 61 , 62 ), leading to oncogenic transformation and tumoral progression. Therefore, the implementation of MKIs drugs in clinical practice determined important clinical implications in many human cancers such as leukaemia ( 63 ), renal carcinoma ( 64 , 65 ) and hepatocellular carcinoma ( 66 , 67 ). Alike, MKIs had extensive applications in thyroid oncology, both in the treatment of radioactive iodine-refractory differentiated thyroid carcinoma ( 68 , 69 ) and in advanced medullary carcinoma ( 57 , 70 ).…”

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

“…It was found that 5–10% of lung cancer patients develop resistance to TKIs due to c-MET gene amplification [ 54 ]. This amplification, leading to ErbB3-dependent PI3K activation, contributes to tumor resistance to gefitinib [ 55 ]. HGF can induce resistance to gefitinib in lung adenocarcinoma patients with EGFR mutations by phosphorylating c-MET and activating the PI3K/Akt signaling pathway through an ErbB3-independent pathway [ 56 ].…”

Differential Response to Sorafenib Administration for Advanced Hepatocellular Carcinoma

“…A combination of immune checkpoint inhibitors and tyrosine kinase inhibitors could be a breakthrough treatment modality, but defects in interferon-γ or insufficient tumor antigen immunosuppressive cells in the tumor microenvironment develop resistance to immune checkpoint inhibitors [ 25 , 26 ]. Sorafenib and other TKIs have been used globally, and molecular biomarkers and genome changes in pathobiological issues have been emphasized [ 27 ]. However, varying outcomes in different metastatic locations have been studied.…”