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Review
. 2021 Oct 13:11:756672.
doi: 10.3389/fonc.2021.756672. eCollection 2021.

Cabozantinib for HCC Treatment, From Clinical Back to Experimental Models

Shanshan Deng  1 , Antonio Solinas  2 , Diego F Calvisi  3
Affiliations
Review

Cabozantinib for HCC Treatment, From Clinical Back to Experimental Models

Shanshan Deng et al. Front Oncol. .

Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Patients with early-stage HCC can be treated successfully with surgical resection or liver transplantation. However, the usual late diagnosis of HCC precludes curative treatments, and systemic therapies are the only viable option for inoperable patients. Sorafenib, an orally available multikinase inhibitor, is a systemic therapy approved for treating patients with advanced HCC yet providing limited benefits. Consequently, new drugs have been developed to overcome sorafenib resistance and improve patients' prognoses. A new promising strategy is using c-MET inhibitors, such as cabozantinib, as activation of c-MET occurs in up to 40% of HCC patients. In particular, cabozantinib, in combination with the checkpoint inhibitor atezolizumab, is currently in phase 3 clinical trial for HCC, and the results are eagerly awaited. Herein, we summarize and review the drugs approved for the treatment of advanced HCC, mainly focusing on the clinical and preclinical efficacy evaluation of cabozantinib. Also, we report the available preclinical data on cabozantinib-based combination therapies for HCC, current obstacles for cabozantinib therapy, and the future directions for cabozantinib-based treatment for HCC.

Keywords: c-MET; cabozantinib; clinically; combination therapy; hepatocellular carcinoma; multikinase inhibitor; preclinical.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Algorithm illustrating the current treatment options (beyond the clinical trials) for patients with advanced HCC. Note that it remains unclear whether or not patients progressing on atezolizumab and bevacizumab benefit from second-line drugs tested such as sorafenib, lenvatinib, ramucirumab, and cabozantinib. Therefore, patients who develop adverse effects leading to the withdrawal of atezolizumab and bevacizumab should be offered the available sequence of targeted therapies.
Figure 2
Figure 2
Schematic representation of the mechanism of action of cabozantinib. Administration of cabozantinib to cancer cells leads to the inhibition of several tyrosine kinases (c-MET, VEGFR2, AXL, c-KIT, c-RET, and FLT3) as well as MDR1/P-glycoprotein in the tumor cell and/or in the endothelial cell. These tyrosine kinases, once activated, induce a plethora of downstream pathways (STAT3, Ras/BRAF/MEK/ERK, AKT/mTOR, PLCγ/PKC, etc.) that lead to several biologic effects on the cells (proliferation, survival, migration, chemoresistance, etc.). These activities are blunted by cabozantinib. Black arrows indicate activation, whereas red blunted arrows indicate inhibition.
Figure 3
Figure 3
Schematic representation of the possible therapeutic strategies coupling cabozantinib to other signaling inhibitors in preclinical models of HCC. It has been previously shown that cabozantinib treatment on HCC cells leads to the compensatory activation (dotted, black line) of the FAK pathway, in which the use of FAK inhibitors can overcome. A synergistic, antineoplastic effect has also been observed when cabozantinib was co-administered to AKT/mTOR inhibitors. In addition, targeting the IGFR1 and FGFR1 pathways might hinder the resistance of cancer cells to cabozantinib administration. A possible synergistic effect could also be achieved with the concomitant treatment with cabozantinib and immune checkpoint inhibitors, although the data in this regard are contradictory (question mark).
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References

    1. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular Carcinoma in Cirrhosis: Incidence and Risk Factors. Gastroenterology (2004) 127(5 Suppl 1):S35–50. doi: 10.1053/j.gastro.2004.09.014 - DOI - PubMed
    1. European Association for the Study of the Liver . Electronic Address Eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. J Hepatol (2018) 69(1):182–236. doi: 10.1016/j.jhep.2018.03.019 - DOI - PubMed
    1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. . Sorafenib in Advanced Hepatocellular Carcinoma. N Engl J Med (2008) 359(4):378–90. doi: 10.1056/NEJMoa0708857 - DOI - PubMed
    1. Reig M, Rimola J, Torres F, Darnell A, Rodriguez-Lope C, Forner A, et al. . Postprogression Survival of Patients With Advanced Hepatocellular Carcinoma: Rationale for Second-Line Trial Design. Hepatology (2013) 58(6):2023–31. doi: 10.1002/hep.26586 - DOI - PubMed
    1. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. . Lenvatinib Versus Sorafenib in First-Line Treatment of Patients With Unresectable Hepatocellular Carcinoma: A Randomised Phase 3 non-Inferiority Trial. Lancet (2018) 391(10126):1163–73. doi: 10.1016/S0140-6736(18)30207-1 - DOI - PubMed