A Case Study on Sotorasib and Zebrafish Oncology Models in KRAS-Driven NSCLC

Non–small cell lung cancer (NSCLC) is one of the most challenging cancers to treat, especially the KRAS G12C mutation which historically known as undruggable target. In this case, Sotorasib has changed this by showing inhibition against the KRAS G12C mutant protein and making it to stay in an inactive GDP-bound state. This action shuts down downstream MAPK signaling which helps in slowing tumor cell proliferation and activation of apoptosis.

Preclinical development of sotorasib involved a set of oncology assays. Tumor growth inhibition (TGI) assays quantified suppression of KRAS-driven tumor expansion. ADME studies showed metabolic stability and favorable pharmacokinetics. MAPK pathway inhibition analyses validated expression of p-ERK, RAF, ME drug mechanism. Apoptosis and proliferation markers including caspase activation and Annexin V staining showed that sotorasib inhibits growth and simultaneously works towards tumor cell death.

Earlier therapies for KRAS mutations often induced adverse events such as renal impairment, QTc prolongation and broad off-target toxicity. While comparing these, sotorasib provides a much safe profile.

The FDA granted approval based on substantial improvements in overall response rate (ORR), duration of response (DOR)and disease control rate (DCR) supported by tolerable and minimal side effects.

Expression levels of EGFR and VEGF in a Zebrafish TNBC Model, illustrating differential response patterns across various groups.

Zebrafish models have now emerged in understanding and optimizing KRAS-targeted treatments. Zebrafish oncology model expressing KRAS G12C develop early-onset tumor proliferation, enabling rapid in vivo drug screening. It allows real-time visualization of tumor growth and volume, angiogenesis and metastasis. Histopathological imaging quantifies tumor burden. Additional assays such as expression of EGFR and VEGF, apoptosis mapping, vascular remodeling analysis and drug penetration using ADME evaluation provides clear visuals of efficacy and toxicity.