Pre-Existing Mutations May Explain Development of Resistance to Targeted Cancer Drugs ► NCI Cancer Bulletin for June 26, 2012 - National Cancer Institute

NCI Cancer Bulletin for June 26, 2012 - National Cancer Institute

Pre-Existing Mutations May Explain Development of Resistance to Targeted Cancer Drugs

Most patients with advanced colorectal cancer treated with the drug panitumumab (Vectibix) develop resistance to the treatment, and a new study suggests why. Even before patients begin the treatment, a small percentage of their tumor cells may harbor genetic mutations that make the tumors resistant to the drug, researchers reported in Nature on June 13.

Colorectal tumors without KRAS gene mutations usually develop resistance to panitumumab within several months. To study why, Dr. Luis Diaz of the Sidney Kimmel Comprehensive Cancer Center and his colleagues analyzed blood samples from 28 patients for common mutations in the KRAS gene that confer resistance to the drug. The blood samples were collected before treatment and at 4-week intervals during treatment.

Four of the 28 patients were known to harbor KRAS mutations in their tumors, and the researchers detected mutant forms of the KRAS gene in blood samples from 3 of these patients before they began treatment. No KRAS mutations were detected in blood samples obtained before treatment from the 24 patients whose tumor tissue was believed to contain nonmutated KRAS.

An analysis of blood samples taken during treatment indicated that 9 of those 24 patients developed KRAS mutations over the course of treatment. The timing of the appearance of the KRAS mutations was consistent with the time it typically takes for panitumumab resistance to emerge, 5 or 6 months.
The researchers used these findings to develop a mathematical model of tumor evolution in patients who initially responded to panitumumab. The model indicated that tumors probably contained cells with KRAS mutations before the patients started panitumumab treatment. Once treatment started, the number of resistant cells increased. The authors suggest that “resistance is therefore a fait accompli.”

The fact that a substantial proportion of patients in the study developed mutations in a single gene suggests that only a limited number of mutations and genes may confer resistance, the researchers noted. This finding is encouraging because it may be possible to avoid resistance by treating patients with drugs that target at least two pathways, they concluded.