PURPOSE: K-ras mutations appear to predict resistance to treatment of NSCLC with EGFR TKIs such as erlotinib. The mechanisms of K-ras mediated resistance is unknown, but K-ras potentially can be targeted by statin drugs. Our goals were to study the mechanisms of erlotinib resistance mediated by K-ras in immortalized cells, as well as the consequence of statin treatment.
METHODS: Human Immortalized Bronchial Epithelial Cells (HBEC) and HBEC with K-ras mutations (Dr. JD Minna, UT Southwestern) were plated for proliferation assays and PGE2 production following treatment with lovastatin, mevalonate, erlotinib and celecoxib. EGFR signaling was assessed by pulsing treated cells with EGF over 0-60 minutes and assaying for pERK and pAkt levels.
RESULTS: Erlotinib markedly reduced the proliferation and pERK signaling of HBEC cells; however, K-ras cells were resistant. Lovastatin reduced K-ras cellular proliferation, which was partially reversed by mevalonate addition. Compared to HBEC cells, K-ras cells had markedly elevated PGE2/COX-2 levels that increased following treatment with lovastatin. PGE2/COX-2 production was reversible by mevalonate. Compared to either agent alone, combination treatment with lovastatin and celecoxib had augmented anti-proliferative effect on K-ras cells. However, the combination of lovastatin and erlotinib did not have augmented anti-proliferation compared to lovastatin alone. Finally, lovastatin and celecoxib in combination, but not alone, reduced both constitutive and EGF induced pERK and pAkt signaling in K-ras cells.
CONCLUSION: K-ras mutant cells are resistant to erlotinib, an effect that may be due to persistent constitutive pERK signaling. K-ras mutants also demonstrated high PGE2/COX-2 levels, which increased following lovastatin treatment. Lovastatin reduced the proliferation of K-ras mutants, and in combination with celecoxib, had an augmented anti-proliferative effect. Furthermore, the combination of celecoxib and lovastatin reduced constitutive and EGF-induced pERK signaling.
CLINICAL IMPLICATIONS: Lovastatin may have a role in the chemoprevention and treatment of NSCLC, in combination with other targeted chemotherapies such as erlotinib and celecoxib.
DISCLOSURE: Sridhar Prasad, None.