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Abstract
Background Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in colorectal cancer (CRC). Patients with KRAS-mutant CRC suffer from rapid progression and poorer prognosis than those with KRAS wild-type CRC. Due to the inefficiency of target therapy such as anti-EGFR inhibitors, CRC patients with KRAS mutation eagerly require more effective therapies
Methods We performed a combined transcriptomic sequence and metabolomic analysis on multiple KRAS-mutant CRC cell lines to explore the characteristics of KRAS-mutant CRC. The core metabolite involved was validated by enzyme-linked-immunosorbent serologic assay (ELISA). The downstream pathways regulated by the core metabolite were identified by RNA-seq and validated by Western Blot assays and immunofluorescence. Then potential targets were further validated in human-derived primary KRAS-mutant CRC organoids, CRC cell line with knocked-in KRAS mutation, and orthotopic mouse models.
Results The depletion of sterol lipids was accompanied by an upregulation of genes involved in the mevalonate pathway in KRAS-mutant CRC after treatment with EGFR inhibitors. The supplementation of MVA pathway inhibitors reversed drug resistance to anti-EGFR therapy in KRAS mutant CRC (IDDF2024-ABS-0231 Figure 1A). The above results were further validated in KRAS-mutant CRC organoids (IDDF2024-ABS-0231 Figure 1B), subcutaneous xenografts, and orthotopic mouse models (IDDF2024-ABS-0231 Figure 1C). Mechanically, we found the geranylgeranyl pyrophosphate (GGPP) is the core metabolite that modulated drug resistance of anti-EGFR therapy in the KRAS mutant CRC. Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy. The inhibitor of geranylgeranyl diphosphate synthase 1 (GGPS1) could enhance the anti-EGFR efficiency in KRAS mutant CRC by altering the lysosomal localization of mTOR to stop cells from entering a DTP state.
Conclusions We found that GGPP/GGPS1 was the core factor regulating the resistance of anti-EGFR therapy in KRAS mutant CRC, which may become a potential synergistic therapeutic target for KRAS-mutant CRC. MVA inhibitors can enhance anti-EGFR efficiency in a pre-clinical CRC organoids and mouse models which broadening the scope of usage for EGFR inhibitors in CRC treatment (IDDF2024-ABS-0231 Figure 1D).