Biomarkers Matter

ARID1A is part of a chromatin remodeling complex (SWI/SNF) that helps regulate gene expression. In most contexts, ARID1A acts as a tumor suppressor, and loss of ARID1A function can contribute to impaired DNA damage response and increased cell proliferation. Some cholangiocarcinoma tumors have loss-of-function mutations in ARID1A. Clinical trials investigating whether ARID1A-mutated cholangiocarcinoma tumors respond to certain therapies, such as DNA-damaging agents, may be available.

Ataxia telangiectasia mutated (ATM) is a tumor suppressor protein that normally helps coordinate the repair of double-strand DNA breaks. Specifically, it helps activate specialized DNA repair processes called homologous recombination and non-homologous end joining. Some cholangiocarcinoma tumors have mutations in ATM that lead to impaired DNA repair and thus persistence of mutations that can drive cancer cell proliferation.

BRCA1 associated protein-1 (BAP1) is a type of protein that protects certain other proteins from degradation, and also plays a role in regulating gene expression. Through these functions, BAP1 helps regulate multiple cellular processes including cell proliferation, response to DNA damage, and cellular differentiation. Loss of BAP1 function can contribute to cancer cell growth, a process that occurs in some cholangiocarcinoma tumors due to BAP1 mutations. There may be clinical trials investigating whether BAP1-mutated tumors are responsive to certain therapies, such as DNA-damaging agents.

BReast CAncer gene (BRCA)1/2 are tumor suppressors that normally facilitate a specific type of DNA damage repair called homologous recombination repair. Although initially described in breast cancer, it may be present in other cancers, like cholangiocarcinoma. Mutations in BRCA1/2 lead to deficits in DNA repair, allowing genomic damage to persist and drive cell proliferation and cholangiocarcinoma growth. Mutations in BRCA1/2 can be inherited and thus present in all cells in the body; they can also occur sporadically (at random) and thus be found only in cancerous cells. Mutations in BRCA1/2 may sensitize cancer cells to certain DNA-damaging therapies (e.g., PARP inhibitors), and there may be ongoing clinical trials. 

B7-H3 and B7-H4 are cell surface proteins that function as “immune checkpoints,” meaning they decrease immune response (particularly T cell response). B7-H3 and B7-H4 have minimal expression in healthy bile duct tissue, but notable expression is sometimes present in cholangiocarcinoma and may allow the tumor to evade immune surveillance. Clinical trials exploring new therapies relevant to B7-H3 or B7-H4 may be available, such as trials of antibody-drug conjugates or new immunotherapy options (e.g., CAR-T cells).

Claudin 18.2 is a protein normally found on stomach cells (gastric mucosa) that helps hold adjacent cells together as part of a structure called tight junctions. Claudin 18.2 is not normally present in healthy bile duct tissue but has been detected in some cholangiocarcinoma tumors. Researchers are still working to understand how Claudin 18.2 may drive cholangiocarcinoma growth, but it may contribute to increased cancer cell invasion of surrounding tissues. Clinical trials investigating may be available, such as studies of antibody-based treatments directed against claudin 18.2.

Epidermal growth factor receptor (EGFR) is a cell surface protein that normally responds to certain growth factors. When bound to an activating growth factor, EGFR turns on downstream signaling pathways (e.g., MAPK/ERK and PI3K/AKT) that ultimately promote cell growth and division. Some cholangiocarcinoma tumors are driven by EGFR mutations that cause constant signaling activation even when no growth factor is bound to the receptor. This results in unregulated proliferation of cancer cells.

Isocitrate dehydrogenase 2 (IDH2) is a metabolic enzyme that converts isocitrate to alpha-ketoglutarate, helping generate usable energy for cells. Some cholangiocarcinoma tumors have mutations in IDH2, which causes the enzyme to aberrantly produce 2-Hydroxyglutarate. 2-Hydroxyglutarate is considered an oncometabolite because it promotes cancer cell growth through mechanisms such as altered gene regulation (epigenetic changes) and decreased tumor immunogenicity. There may be clinical trials investigating small molecule inhibitors of mutated IDH2 in cholangiocarcinoma.

Note: IDH2 is similar to IDH1, but is located in a different part of the cell. IDH1 targeted therapies do not work on IDH2 mutations (unless specifically stated, e.g., “dual IDH1/IDH2”).

KRAS is a signaling protein that is “off” when bound to GDP (guanosine diphosphate) and “on” when bound to GTP (guanosine triphosphate). Certain growth factors normally activate KRAS, leading to activation of downstream signaling pathways (e.g, MAPK/ERK and PI3K/AKT) that promote cell proliferation. Some cholangiocarcinoma tumors harbor mutations in KRAS, which lead to KRAS being stuck in the GTP-bound “on” conformation. This leads to uncontrolled proliferation of cancer cells. Trials. Clinical trials may investigate small-molecule inhibitors of KRAS in cholangiocarcinoma.

MDM2 amplification is a genetic change in some cholangiocarcinoma tumors that causes too much MDM2 protein to be generated in cells. Excess MDM2 decreases p53, which is needed to respond to DNA damage by either coordinating repair or inducing cell death. Impaired p53 function due to MDM2 amplification thus allows persistence of DNA damage, which can drive cancer cell growth. Clinical trials evaluating small-molecule inhibitors of MDM2 may be available.

Nectin-4 (also called PVRL4) is a cell surface protein that facilitates cell-cell adhesion in embryonic tissue and a limited number of adult tissue types, but it is not normally expressed at significant levels in healthy bile duct tissue. In contrast, some cholangiocarcinoma tumors have high levels of Nectin-4, which may facilitate cancer cell proliferation, adhesion, and migration. It may also affect anti-tumor immunity. Clinical trials of nectin-4-targeted therapies (e.g., antibody-drug conjugates) may be available.

PD-L1 is an immune checkpoint protein found on cell surfaces that blocks immune response. Cancer cells can express PD-L1, which can bind to PD-1 on immune cells (especially T cells) to inhibit anti-tumor immune response and allow unchecked tumor growth. Clinical trials investigating new immunotherapy options, including combination therapies, for the treatment of PD-L1 high tumors may be available.

Note: Anti-PD-L1 immunotherapies such as durvalumab and pembrolizumab are FDA-approved in combination with gemcitabine and cisplatin as a first line therapy for all patients with advanced / metastatic cholangiocarcinoma, regardless of biomarker status. A major clinical trial (TOPAZ-1) found that addition of durvalumab to gemcitabine/cisplatin was beneficial regardless of tumor PD-L1 status.

PTCH1 is a cell surface protein that functions as a negative regulator of the Hedgehog signaling pathway, which is important for embryonic development but much less active in most adult tissues (exceptions include stem cells and progenitor cells). Some cholangiocarcinoma tumors have loss-of-function mutations affecting PTCH1, leading to aberrant activation of the Hedgehog pathway and potentially contributing to tumor growth. There may be clinical trials studying small-molecule inhibitors of Hedgehog pathway signaling proteins (e.g., SMO) for the treatment of tumors with PTCH1 mutations.

Phosphatase And Tensin Homolog (PTEN) is a tumor suppressor that decreases activation of PI3K-AKT/mTOR, a signaling pathway involved in cell proliferation. Loss-of-function PTEN mutations occur in some cholangiocarcinoma tumors and may contribute to cancer cell proliferation. There may be clinical trials available investigating treatment strategies for tumors with PTEN mutations, such as small-molecule PI3K-AKT/mTOR inhibitors.