How many times have you watched a prescription drug commercial projecting happy and healthy-looking people living life to the fullest? I’m sure you’ve noticed towards the end, the voice-over artist suddenly speeds up the dialogue detailing the not-so-glamourous side effects of said drug that may include fatigue, nausea, diarrhea, constipation, etc. When it comes to anti-cancer therapy agents, some of the more severe side effects are secondary cancers. For example, certain chemotherapy drugs have been associated with myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and acute lymphocytic leukemia (ALL)1.
Off-target toxicity of cancer therapeutic drugs that cause severe side effects have been the cause of clinical trial failures. Many research scientists have faced the conundrum of studying proto-oncogenes or tumor suppressor genes in one tissue only to have repercussions in others. Therefore, delivering a therapeutic systemically could cause harm to other organs, even though it may treat the primary disease. To overcome these obstacles, targeted molecular therapy has made its grand entrance in precision medicine and new targetable genes are identified and tested in research labs all over the world.
“Oncochannels” are ion channels that play a role in the development of many types of cancers2. Voltage-gated potassium (Kv) channels are the largest group among the ion channel family involved in neural communication and muscle contractions; the heart being the most important muscle in the body. When these channels become abnormal, homeostatic cellular processes are deregulated which can lead to cancer cell proliferation, migration, and disruption to the extracellular-matrix3.
Pharmacological compounds that block aberrant Kv channel activity have been introduced as potential cancer therapeutics. However, considering the importance of Kv channels to the nervous and cardiac systems, this may not be the most practical approach due to the possibility of severe off-target effects. In this article, we present a novel “electrically-silent” voltage-gated potassium (KvS) channel, KCNF1, and its role in lung cancer that may overcome this quandary.
To highlight, KCNF1 falls in the family of KvS channels. KvS channels behave dissimilarly to their Kv counterparts and are less widely known and studied in cancer. We found that KCNF1 is upregulated in human lung tumors and non-small cell lung cancer (NSCLC). Downregulation of KCNF1 in lung adenocarcinoma cell lines reduced cell proliferation, migration, and tumor progression in mouse xenografts. Silencing KCNF1 in a NSCLC cell line displayed a more non-transformed phenotype with re-establishment of the basement membrane (video). Where most Kv and KvS channels are localized in the membrane to regulate membrane potential, KCNF1 is discovered to be in the nucleoplasm to regulate gene expression. Lastly, a KCNF1 target, ITGB4, identified in this paper is a known oncogene that is aberrantly expressed in several cancers, including lung cancer.
By the end of 2022, approximately 240,000 people will be diagnosed with lung cancer; enough people to fill permanent seats at the Indianapolis Motor Speedway, the largest sports seating facility in the world4. Of those diagnosed, approximately 130,000 people will die from this disease4. Although lung cancer mortality rates have dropped by 5% between 2015 and 2019 as a result of early screening, smoking cessation campaigns, and advancements in therapeutic approaches, it remains the leading cause of cancer deaths among men and women across the U.S.5 Hence, it is our duty as research scientists to identify new strategies and interventions to improve the outcomes of lung cancer patients. Due to the non-canonical nature of KCNF1 as an “electrically-silent” voltage-gated potassium ion channel, we believe that we are closer to creating a possible therapeutic targeting an ion channel for the treatment of lung cancer without adverse off-target effects.