Although some members of the public might think of “cancer research” as an indivisible whole, the reality is that studies into different cancers are at different stages of achieving the threshold for a breakthrough. Part of what makes cancer research so tedious (yet exciting) is that there is just so much more to discover about the mechanisms of how some cancers come to be and what we can do about them.
A significant hurdle that cancer researchers are presented with is that some cancers, such as cholangiocarcinoma (CCA), are often detected only at advanced stages of the disease. Given that the only potential cure so far is surgical, it is critical for patients with CCA to be diagnosed early while the tumor remains resectable. When the CCA has developed past the point of resectable disease, all other treatment options are mostly palliative.
We have established that early diagnosis is key, but is there hope for the vast majority of patients who only present at advanced stages of the disease? Sarkis and colleagues wrote a review on the various treatment regimes being explored to target and treat advanced CCA. The study by this Lebanese team of researchers challenges us to look beyond surgical treatments to other novel targeted therapies that are currently being developed.
Challenging Conventional Thinking
Sarkis et al described a few key facts about CCA as we understand them today:
- The incidence of intrahepatic CCA in Western countries has been increasing for the last 2 decades; the cause of this is unknown.
- Among the different areas where CCA can arise, distal tumors have the highest resectability rates.
- Even in CCA patients for whom surgery remains a viable option, there is still a high risk of local and distal recurrences.
- The median survival is less than 2 years for patients with advanced CCA.
- There currently is no standard, guideline-approved treatment for advanced CCA.
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Although these facts concerning advanced CCA look grim, there is a sliver of hope. The research team wrote, “since the description of a variety of molecular defects involving oncogenes and tumor suppressor genes, inducing the conversion of [CCA’s] precursors (intraductal papillary mucinous neoplasm and biliary intraepithelial neoplasia) to a malignant tumor, by a stepwise accumulation of genetic abnormalities, clinical trials have been designed to study the molecular identity of the CCA and to explore targeted therapy.”
In other words, the ways in which we are thinking about cancer are changing, and, therefore, our clinical studies are too. Medical researchers are now focusing on the genetic abnormalities and aberrant signaling pathways associated with cancer and developing targeted therapies to neutralize these conditions.
The RAS-RAF-MEK-ERK Pathway
One of these pathways that we will look at in some detail is the RAS-RAF-MEK-ERK pathway. Barbosa and colleagues, in a paper reporting on the work in progress to target this pathway in cancer research, wrote, “The RAS-RAF-MEK-ERK pathway is the most well-studied of the mitogen-activated protein kinase (MAPK) cascades and is critical for cell proliferation, differentiation, and survival.” They added that “abnormalities in regulation resulting from mutations in components of this pathway, particularly in upstream proteins RAS and RAF, are responsible for a significant fraction of human cancers.”
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Sarkis and colleagues agree. They wrote, “Studies have shown that mutations in the MAP kinase pathway: Ras/RAF/MEK/ERK signaling pathways are frequent in CCA” and that they “promote neoplastic proliferation, differentiation, migration, and metastasis.”
One of the therapeutic options when targeting this pathway is to inhibit MEK in KRAS-mutant CCA. A medication that does this is binimetinib, a selective inhibitor of MEK 1/2. Preclinical data suggest that binimetinib offers clinical benefits to patients with advanced CCA when combined with chemotherapy. However, attempts to prove this through clinical trials have failed; a study combining binimetinib with gemcitabine and cisplatin did not result in improvements in progression-free survival or overall survival.
Another drug, selumetinib, is a MEK 1/2 and interleukin (IL)-6 inhibitor. A clinical trial using it as a single-drug treatment for advanced biliary cancer demonstrated a median overall survival of 9.8 months and tolerable toxicity. In addition, it appears to be associated with muscle gain and muscle anabolism, meaning that it can potentially be used to reduce cancer-induced cachexia.
Following the Evidence
The RAS-RAF-MEK-ERK pathway is a MAPK cascade that has also been targeted in other cancers. However, the emphasis on the various parts of this pathway has been uneven. Barbosa et al wrote, “Despite extensive efforts in developing clinically promising inhibitors, determining structures, and unveiling activation mechanisms for upstream MAPK components, relatively little focus has been directed towards understanding and elucidating the functional interactions of the downstream kinases, MEK and ERK.”
This means that drugs like binimetinib and selumetinib that do target the downstream kinase MEK could potentially unlock further opportunities in cancer treatment, should research continue. “Relatively recent efforts to explore alternative therapeutic strategies produced the RAF-MEK inhibitor combination therapy, which was capable of prolonging responses and delaying the emergence of resistance in patients,” Barbosa and colleagues wrote.
The RAS-RAF-MEK-ERK pathway represents one of the many areas of cancer research. In the future, these treatments may become as prominent as chemotherapy in treating CCA and other cancers.
Sarkis Y, Al Soueidy A, Kourie HR. Will advanced cholangiocarcinoma become a targetable malignancy? Crit Rev Oncol Hematol. 2021;159:103233. doi:10.1016/j.critrevonc.2021.103233
Barbosa R, Acevedo LA, Marmorstein R. The MEK/ERK network as a therapeutic target in human cancer. Mol Cancer Res. 2021;19(3):361-374. doi:10.1158/1541-7786.MCR-20-0687