Hypoxia-activated prodrugs (HAPs) prevented treatment resistance when combined with standard treatment in a mathematical model of EGFR mutation–driven non-small cell lung cancer (NSCLC), according to study results published in PLOS Computational Biology.1

HAPs are designed to reach the low-oxygen patches of solid tumors that standard drugs have difficulty reaching; however, in clinical trials, these drugs have yet to show significant benefits for patients. Therefore, a team of researchers from the University of Minnesota and the University of Southern California sought to find a way to enhance the effectiveness of HAPs.

Using a mathematical model of EGFR mutation–driven NSCLC, the researchers monitored the development of drug resistance. Standard treatment for this subtype of lung cancer is erlotinib, and resistance to treatment develops in most patients with this subtype 12 to 18 months after initiating treatment.

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The team tested various dosages and treatment schedules of erlotinib with the HAP evofosfamide to determine which regimen showed the greatest promise in preventing resistance in the virtual tumor cells.

Results demonstrated that combining the 2 drugs more effectively delayed resistance than using either drug alone; sequentially alternating the drugs resulted in further reduced drug resistance and minimal tumor burden; and strategies that decreased the time between each evofosfamide dose and the next erlotinib dose further reduced tumor burden.

These study results suggest an optimal treatment regimen for patients with this subtype of NSCLC; however, these findings need to be validated in preclinical tests before clinical trials with patients can be initiated, explained the researchers.


1. Lindsay D, Garvey CM, Mumenthaler SM, Foo J. Leveraging hypoxia-activated prodrugs to prevent drug resistance in solid tumors. PLoS Comput Biol. 2016 Aug 25. doi: 10.1371/journal.pcbi.1005077. [Epub ahead of print]