Cancer Letters

Cancer Letters

Volume 460, 28 September 2019, Pages 1-9
Cancer Letters

Targeted therapy for hepatocellular carcinoma: Challenges and opportunities

https://doi.org/10.1016/j.canlet.2019.114428Get rights and content

Highlights

  • Despite the emergence of targeted therapy, advanced-stage HCC remains largely incurable due to therapeutic resistance.

  • Multiple factors contribute to drug resistance of HCC patients against MKIs.

  • Further studies are expected to identify biomarkers for response and promote efficacy of immunotherapy.

  • Insight into heterogeneity of HCC and combined therapy could be the next step forward the future of precision medicine.

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, which ranks as the sixth of cancer-related death. Despite the emergence of targeted therapy, advanced-stage HCC remains largely incurable due to low response rate and therapeutic resistance. In this review, we mainly focused on the current progression of multi-kinase inhibitors and immunotherapies in the treatment of HCC. We highlight the mechanism underlying the ineffectiveness of these targeted therapies, including oncogenic alterations in driver genes and downstream pathways, high heterogeneity of HCC, and the mutual interaction of tumor microenvironment that promotes therapeutic resistance. We also discussed how these previous studies suggested for future therapeutic strategies. Besides, the complexity of HCC heterogeneity and cancer revolution need to be recognized in personalized therapy. Establishment of a drug screening system and identification of biomarkers of response is also in urgent need to overcome drug resistance. Meanwhile, a combination of targeted therapies could also be explored as a promising strategy in the future.

Introduction

Liver cancer is the sixth most commonly diagnosed cancer, with about 841,000 newly diagnosed cases and 782,000 deaths annually [1]. Hepatocellular carcinoma (HCC), accounting for about 80% of primary liver cancer, is the major pathological type. According to CONCORD-3 data reported by the Lancet, for most cancers, the survival trends are generally increasing due to the access to early diagnosis and optimal treatment. However, in most countries, liver cancer survival has changed very little during the 20-year period (1995–2014). The five-year net survival rate of liver cancer was in the range of 5–30% throughout 2000–2014. Take China for an example, the survival rate was 11.7% during 2000–2004, only increased to 14.1% during 2010–2014 [2]. In fact, the majority of HCC patients are diagnosed in advanced-stage, at which point surgical treatments (resection and transplantation) and locoregional treatment (chemoembolization) have been disappointing in terms of patients' overall survival [3]. Meanwhile, traditional chemotherapies, such as 5-fluorouracil, cisplatin, doxorubicin, or gemcitabine, haven't shown promising outcomes. Therefore, the development of effective targeted therapy for advanced HCC is in urgent need.

In 2007, a multi-kinase inhibitor (MKIs), sorafenib, was approved as the first systemic agent for the treatment of advanced unresectable HCC as Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial had suggested a survival benefit of about 3 months [4]. Since then, a glimmer of hope for unresectable advanced HCC has attracted various clinical trials testing for candidate targeted drugs. Currently, three oral multi-kinase inhibitors, sorafenib, regorafenib and lenvatinib, have been approved as first-line or second-line therapy for advanced HCC [5]. For immunotherapy, an anti-PD-1 monoclonal antibody, Nivolumab, has been granted accelerated approval from Food and Drug Administration (FDA) to treat advanced HCC based on promising results from a phase II trial (Checkmate-040) [6]. Also, other targeted therapies, such as GPC3 based CAR-T and AMPK inhibitors are also under exploration [7,8].

Despite those promising data in clinical trials, targeted therapies still confronted with problems like low objective response rate (ORR) and adaptive or acquired resistance [4,[9], [10], [11]]. These unsatisfied outcomes mainly result from heterogeneity of HCC derived from its morphological diversity, signal transduction network and microenvironmental discrepancies etc [12,13]. Thus, researches on biomarkers of liver cancer classification, biomarkers of response and how to deal with cancer revolution within tumors during therapy are still expected. In this review, we summarized the recent targeted therapies for HCC, mechanisms on resistance and potential strategies to overcome low efficacy of current therapies, in hope of shedding light on precision medicine for HCC in future researches.

Section snippets

Introduction of multi-kinase inhibitors

Sorafenib, an oral multikinase inhibitor (MKI), which blocks tyrosine kinase receptor (VEGFR-2/3, PDGFR-β, c-Kit, FLT-3, RET), downstream pathway kinase (Ras/Raf/MEK/ERK, JAK/STAT) activities and other targets (c-Raf, B-Raf), is the first approved systemic agent for advanced liver cancer (Fig. 1) [[14], [15], [16]]. According to SHARP trial, sorafenib showed a 2.8-month prolonged survival for patients compared with the placebo group, with a median overall survival (OS) of 10.7 months versus 7.9

CAR-T

Cancer immunotherapy is named as Breakthroughs of the Year by Science in 2013 due to the progress made in two fields: chimeric antigen receptor (CAR)-modified T cells and checkpoint inhibitors. CAR-T have been heralded as a promising technology due to the substantial benefit observed in patients with relapsed or refractory B-cell malignancies [[84], [85], [86], [87]]. The success of CAR-T has encouraged many resources worldwide to recognize additional tumor-associated antigens aiming to extend

Perspectives

The development of HCC is a multistep process with a complex interaction of altered signaling pathways, tumor microenvironment, and varied genetic background, leading to high tumoral heterogeneity, which posed a great challenge to precision medicine. With the advancement in multi-omics and gene editing technology, precision medicine has brought hope to the previous “uncurable” patients. However, it's undeniable that we have faced with many bottleneck issues followed with the approval of the new

Acknowledgment

We gratefully acknowledge the support from the National Natural Science Foundation of China (81802878, 81722034, 81572896) and Shanghai Sailing Program (18YF1400200). It is also sponsored by National Major Scientific and Technological Special Project for “Significant New Drugs Development”& “Prevention and Control of Infectious Diseases” (2018ZX09101-002; 2017ZX100203205004).

Conflicts of interest

The authors have no conflict of interest to disclose.

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