Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

Abstract

Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent late diagnosis of this form of cancer, which makes surgical removal of the tumor impossible, together with the poor response to standard chemotherapy and targeted therapy with inhibitors of tyrosine kinase receptors. The discovery of genetic alterations with an impact on the malignant characteristics of CCA, such as proliferation, invasiveness, and the ability to generate metastases, has led to envisage to treat these patients with selective inhibitors of mutated proteins. Moreover, the hope of developing new tools to improve the dismal outcome of patients with advanced CCA also includes the use of small molecules and antibodies able to interact with proteins involved in the crosstalk between cancer and immune cells with the aim of enhancing the immune system’s attack against the tumor. The lack of effect of these new therapies in some patients with CCA is associated with the ability of tumor cells to continuously adapt to the pharmacological pressure by developing different mechanisms of resistance. However, the available information about these mechanisms for the new drugs and how they evolve is still limited.

Identification of Key Genes Related to Lung Cancer with Brain Metastasis through Weighted Gene Correlation Network Analysis

“…If the ROS1 gene is mutated, it will cause cancer cells to drive up, which is the culprit of tumor occurrence. Glioblastoma [24], in ammatory myo broblastoma [25,26], cholangiocarcinoma [27], ovarian cancer [28], gastric cancer [29], colorectal cancer [30], angiosarcoma [31], arachnid melanoma [32] and non-small cell lung cancer [33] are all present with ROS1 fusion protein. Today, ROS1 is a proven therapeutic target for NSCLC.…”

Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions

“…The heterogeneity in expression levels of molecular targets can predict the lack of effect of some drugs in CCA and this heterogeneity may potentially be used to select the best treatment. Resistance is a dynamic process and tumours, in response to the exposure to drugs, can change the levels of the proteins involved in resistance123 124; therefore, the occurrence of mutations that affect the activity of these proteins can also induce cross-resistance to different drugs 125. New mutations in tyrosine kinase receptors and other targets are considered a mechanism of acquired resistance to targeted agents and are responsible for disease progression after an initial response 123.…”

“…Resistance is a dynamic process and tumours, in response to the exposure to drugs, can change the levels of the proteins involved in resistance123 124; therefore, the occurrence of mutations that affect the activity of these proteins can also induce cross-resistance to different drugs 125. New mutations in tyrosine kinase receptors and other targets are considered a mechanism of acquired resistance to targeted agents and are responsible for disease progression after an initial response 123. Reduced expression of programmed cell death ligand 1 (PD-L1) has been associated with worse outcome in patients with CCA treated with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), nivolumab or pembrolizumab 126 127…”

An Insight into the Novel Immunotherapy and Targeted Therapeutic Strategies for Hepatocellular Carcinoma and Cholangiocarcinoma

“…Inhibition of PD-L1, via the use of durvalumab, is studied in phase I/II clinical trial, however single use of durvalumab for CCA is not studied yet, in comparison with its utilization as monotherapy in HCC, which presented a moderate improvement for HCC, compared to other ICIs. There is a relatively recent PD-1 and TGF-b inhibitor, bintrafusp alfa or M7824, which proved efficient for immune-resistant CCA, while there is a clinical trial in phase I that is currently performed (NCT02699515), for cases of recurrent CCA after the utilization of first-line chemotherapeutic agents, with 12.7 months, median overall survival [ 72 , 73 ]. Some of the immunotherapeutic drugs are demonstrated in Table 2 .…”