Natural products from Streptomyces cavourensis as candidate modulators of EGFR and KRAS signaling in lung cancer

Lung cancer pathogenesis and progression is commonly driven by dysregulated EGFR and KRAS signaling pathways. To systematically identify natural product modulators of these targets, we employed an integrated silico pipeline focused on the marine bacterium Streptomyces cavourensis . Initial genome mining revealed 31 biosynthetic gene clusters (BGCs), indicating a rich reservoir of putative secondary metabolites. Following structure-based computational screening against three critical lung cancer targets (TP53, EGFR, and KRAS), seven candidate metabolites were prioritized. Among these, the flavonoid naringenin demonstrated strong multi-target binding, with notable affinity for EGFR (-8.6 kcal/mol), while geosmin showed interaction with EGFR's Cys797, a residue linked to tyrosine kinase inhibitor resistance. Comprehensive in silico ADMET profiling indicated favorable drug-like properties for both leads, including high predicted intestinal absorption for naringenin. Furthermore, phylogenetic and sequence conservation analyses of vertebrate EGFR and KRAS orthologues revealed >95% conservation within key functional domains, particularly in structurally constrained regions associated with ligand binding and signal transduction, thereby supporting the biological relevance of these targets and the translational potential of compounds interacting with these conserved sites. In addition, a machine-learning-based QSAR model predicted activity in the low-micromolar to sub-micromolar range, within the limits of the QSAR model. Collectively, this study establishes an effective genome-guided discovery strategy, positions S. cavourensis as a promising source for anti-lung cancer agents, and highlights naringenin and geosmin as prime candidates for further experimental validation in targeting oncogenic signaling.