Combined Therapy May Overcome Cancer Drug Resistance

Gefitinib resistance may be overcome by another inhibitor

MONDAY, June 23 (HealthDay News) -- A network of signaling is disrupted in cancer cells resistant to gefitinib, and combination treatment with gefitinib and another inhibitor may be able to overcome this resistance, researchers report in the June 20 issue of the Journal of Clinical Investigation.

Marta Guix, M.D., from Vanderbilt University School of Medicine in Nashville, Tenn., and colleagues generated squamous cancer cells resistant to gefitinib, which inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase, to examine mechanisms of resistance.

The researchers found that the resistant cells had hyperphosphorylation of the insulin-like growth factor-1 receptor (IGFIR) and the constitutive association of two proteins. This association was disrupted when IGFIR signaling was inhibited, allowing gefitinib to inhibit cell growth in its normal fashion. The resistant cells also had markedly reduced levels of two IGF binding proteins, and addition of one protein allowed gefitinib to inhibit cell growth normally. Mice bearing these resistant tumors did not have recurrence if they were treated with both gefitinib and an antibody against IGFIR.

"These data suggest that loss of expression of IGF binding proteins in tumor cells treated with EGFR tyrosine kinase inhibitors derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists," Guix and colleagues conclude. "Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation."

One of the study authors reports a financial relationship with Merck.

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