Sotorasib resistance in KRAS G12C-mutant invasive mucinous adenocarcinoma with implications for VEGF-A

Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with a poor prognosis. Compared to non-small cell lung cancer, IMA more frequently harbors KRAS mutations in the order p.G12V, p.G12D, and p.G12C. This report describes a patient with a KRAS p.G12C-mutant IMA treated with sotorasib. To date, no studies have investigated the therapeutic efficacy or resistance mechanisms of sotorasib in IMA. The patient was treated with carboplatin and pemetrexed, followed by sotorasib upon disease progression. While the primary lung lesions responded well, metastatic thoracic lymph node lesions continued to increase. A pathological autopsy was performed with the family's consent to investigate potential resistance mechanisms. RNA sequencing and additional analyses revealed increased VEGF-A expression in metastatic lymph node lesions, suggesting a role in sotorasib resistance. These findings provide insights into the potential molecular mechanisms underlying treatment resistance in KRAS p.G12C-mutant IMA.