Real-time dissection of SCLC emergence in a KRAS G12C LUAD tumour: A case study of targeted therapy resistance

Background: Lineage plasticity is an emerging mechanism of resistance in non-small cell lung cancer (NSCLC). We present a case study of a KRASG12C-mutant lung adenocarcinoma (LUAD) PDX that underwent neuroendocrine transdifferentiation into small-cell lung cancer (SCLC) after treatment with the KRASG12C inhibitor sotorasib. Methods: KRASG12C PDX CBX336 was treated with sotorasib and monitored using high-content imaging, fluorescence lineage tracking, DNA barcoding, and whole-exome clonal tracing. Pre- and post-treatment tumours underwent genomic, transcriptomic, and morphometric profiling. PDX-derived ex vivo cultures supported functional studies, including CRISPR knockout and cDNA overexpression. Results: CBX336 showed an initial response to sotorasib followed by rapid regrowth. Post-treatment samples demonstrated a histologic shift from LUAD to SCLC, marked by elevated NEUROD1 and neuroendocrine markers. Lineage tracking revealed a coordinated, not stochastic, transition toward the neuroendocrine state. Multi-omic analysis identified ZEB1 as an upstream regulator linked to RB1 loss, increased p16, and N-cadherin. ZEB1 knockout suppressed neuroendocrine marker induction and partially restored LUAD-like differentiation, confirming ZEB1 as a driver of lineage reprogramming. Conclusions: This case study shows that KRASG12C-targeted therapy can induce neuroendocrine transdifferentiation via ZEB1 upregulation. Real-time monitoring of CBX336 evolution reveals actionable plasticity mechanisms and supports development of strategies to prevent or reverse therapy-induced SCLC emergence.