Researchers demonstrated that lapatinib not only inhibits the growth of cholangiocarcinoma (CCA) with overexpressed human epidermal growth factor receptor 2 (HER2) but can also bypass the chemoresistance presented after gemcitabine treatment, as published in Frontiers in Oncology.

Bai et al conducted a study to determine the effect of lapatinib, an oral tyrosine kinase inhibitor selective for HER2, and a lapatinib-gemcitabine combination treatment on CCA using organoid and cell line models. Moreover, the authors analyzed cell cycle arrest, apoptosis, and proteins involving HER2-dependent downstream signaling pathways to assess the effect of lapatinib on HER2+CCA.

Because this drug exerts antitumor effects on HER2-overexpressed CCA cells while simultaneously overcoming ABCB1-mediated chemoresistance, these results confirm that a lapatinib-gemcitabine combination-based therapy can be significantly more effective at treating these cases.

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“However, because only a small portion of patients with CCA exhibit sensitivity and the median [progression-free survival] is only about 5.3-7.7 months for those receiving gemcitabine-based chemotherapy, initial and acquired drug resistance often results in recurrence, ultimately preventing it from being used extensively,” the authors wrote.

Nonetheless, gemcitabine proved to upregulate ABCB1, which the main substrate seems to be dFdCTP, an active metabolite of gemcitabine that can be expelled from tumor cells. Furthermore, the authors verified that increasing levels of ABCB1 expression reduced the intracellular drug concentration, resulting in gemcitabine resistance.

Given these findings, this study provides a preclinical rationale for further clinical investigation regarding the effectiveness of combining lapatinib with gemcitabine in HER2-overexpressed CCA. 

CCA is the second most frequently occurring hepatobiliary malignancy after hepatocellular carcinoma. Because most patients are asymptomatic at first and often only have a diagnosis at advanced stages, an overall dismal prognosis is common. Recent breakthroughs in CCA genomics have led to the discovery of many unique identified mutations, of which HER2 is overexpressed specifically in cases of extrahepatic CCA.


Bai Z, Guo Z, Liu J, et al. Lapatinib Suppresses HER2-Overexpressed Cholangiocarcinoma and Overcomes ABCB1– Mediated Gemcitabine Chemoresistance. Front Oncol. Published April 8, 2022. doi:10.3389/fonc.2022.860339