Author: Arvind Kaulsay
Affiliation: National University of Singapore, Singapore
Date: 12 May 2025
Before diving into this writing, it is important to understand the function of a biomarker and its forms. In essence, a biomarker is a molecule found within the body that can be used to gauge the state and wellness of the human body. The simplest example would be any analyte that is tested for in a clinical biochemistry panel (RBC, WBC Count, Lipid profile, Liver enzymes, etc.) can serve as a biomarker.
Biomarkers are of different types depending on their significance and the role they play. Some are therapeutic, some can be prognostic- used to identify the rate of disease progression and relay disease prognosis, and lastly, some biomarkers are predictive (Califf, 2018).
Predictive biomarkers permit the identification of patients with a higher probability of responding or not to a specific treatment. Predictive biomarkers play an undermined role in life-debilitating diseases, such as but not limited to hyperlipidemia, diabetes and cancers because such illnesses require heavy medical treatment, and its efficiency depends on the presence or absence of such predictive biomarkers.
In the case of cancer, chemotherapy has been named the “gold standard” method to battle oncogenesis. However, chemo regimens usually consist of a heavy cocktail of chemotoxic agents, and while they may work for some people, most cancer-ridden patients are unable to find solace in these regimens (Gurba et al., 2022). This has urged scientists and physicians to go beyond their scope and identify predictive biomarkers specific to each patient, thereby allowing precision treatment, tailored to each patient and their individual cancer.
The biomarker and focus of this article will be the Kirsten Rat Sarcoma Virus (KRAS), a predictive biomolecule that was first discovered in 1982 to be a 188 or 189-amino-acid-long protein chain that plays a pivotal role in the regulation of cellular activities and signaling (Tatu Pantsar, 2019).
Figure 1: The KRAS pathway (Santarpia et al., 2023)
The image above illustrates just how vital KRAS is in downstream cell signalling. Essentially, KRAS acts like a molecular switch, cycling between an ON and OFF state, KRAS-GTP and KRAS-GDP bound respectively (Santarpia et al., 2023). How this works is, if there is no stimulus at the cell-membrane receptors, along with intrinsic GTPase activity [the process of hydrolyzing guanosine triphosphate (GTP) to guanosine diphosphate (GDP)] of KRAS molecule to swap GTP for GDP, KRAS is in its “off” phase, and there is no downstream signaling that occurs.
Now, given a stimulus, like EGF in an EGF receptor, KRAS is notified and now favors GTP over GDP and conforms to its “on” form. This conformational change in KRAS dynamics signals the MAPK and PI3K-AKT pathway downstream which drives cell proliferation & growth, movement, cell survival and its inverse, cell apoptosis (Simanshu, Nissley, & McCormick, 2017).
How KRAS Functions as a Predictive Biomarker in Cancer
KRAS mutations are greatly associated with Non-Small Cell Lung Cancer (NSCLC), metastatic colorectal cancer (mCRC), and pancreatic duct adenocarcinoma (PDAC) cancers, which has made KRAS a highly sought after predictive biomarker and has earned its name as the “holy grail” (Yang, Zhang, Huang, & Chu, 2023).
Most of these cancers were treated using EGFr antibodies or EGFr inhibitors yet showed persistent growth and metastasis. These treatments proved to work for those who are wild-type for KRAS but are futile for the rest as they have mutated KRAS proteins that remain in an “on” phase regardless of EGFr disturbance (Meng et al., 2021).
With the help of KRAS detection assays such as Next Generation Sequencing, KRAS strip assay or even Sanger sequencing, scientists were able to determine the presence or absence of KRAS, thereby allowing physicians to curate personalized therapy plans catered to each individual instead of using a “one fits all” approach.
It was just 4 years ago when KRAS became a therapeutic biomarker. On the 28th of May 2021, AMG510, market name Sotorasib, was approved by the FDA for the treatment of KRAS G12C (glycine to cysteine) mutations (Huang, Guo, Wang, & Fu, 2021). This drug would lock the mutant protein in an inactive state, thereby decreasing functional KRAS.
A study in Madrid showed the effects of combined therapy using AMG510 along with Panitumumab, an EGFR antibody used to treat mCRC and found prolonged progression-free survival (PFS) in G12C mutated mCRC cases (Fakih et al., 2023).
If anything, this is a testament to the power of modern science and precision therapy. Such ground-breaking discoveries are not “per-chance”, but a result of consistency and domain knowledge paired with accurate, high-throughput screening methods such as Next Generation Sequencing.
This advancement in cancer therapy has revolutionised the game and will serve as a stepping stone for future medical breakthroughs.
References
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Fakih, M. G., Salvatore, L., Esaki, T., Modest, D. P., Lopez-Bravo, D. P., Taieb, J., … Pietrantonio, F. (2023). Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. New England Journal of Medicine, 389(23), 2125–2139. https://doi.org/10.1056/nejmoa2308795
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