Two recently approved leukemia drugs could be enlisted against treatment-resistant lung cancer, according to a new study in Nature Chemical Biology. A clinical trial is expected to launch in Toronto, Canada, and Zagreb, Croatia, later this year to evaluate 1 of them.

The study was performed using a new live cell-based method for identifying small molecules that target specific mutations in cancer cells, developed by researchers at the Donnelly Center for Cellular and Biomolecular Research.

Gilteritinib and midostaurin, 2 drugs approved for patients with leukemia, were identified as potential treatments for lung cancer patients with triple mutant epidermal growth factor receptor (EGFR).

Gilteritinib will be tested in a pilot trial of approximately 20 patients with lung cancer whose tumors harbor the C797S mutation. If proven successful, gilteritinib could become a new standard of care treatment for approximately 60,000 patients with lung cancer and triple mutant EGFR.

Lung cancer is the leading cause of death from cancer in the world and non-small cell lung cancer is the most common type of disease, with approximately one-fifth of cases in North America caused by EGFR mutations.

There are dozens of approved kinase inhibitor drugs that target specific mutations in the receptor’s catalytic domain, but tumors quickly gain new mutations and become drug resistant. One-third of patients with lung cancer on osimertinib, a last resort drug approved in 2017 against double mutant EGFR, will develop the treatment-resistant C797S mutation within 6 to 9 months.

The researchers have developed a method to target the mutations that arise in response to treatment by testing potential drug molecules directly in living cells called Mammalian Membrane 2-Hybrid Drug Screen (MaMTH-DS). The method identifies drug candidates that both enter the cells and target the receptors in their natural environment.

Additionally, MaMTH-DS allows identification of drug molecules that target not only the receptor’s kinase activity, but also its interactions with other cellular proteins.

In a proof of principle study, the research team looked for small molecules that can target the resistance-conferring C797S mutation in the triple mutant EGFR. A screen of nearly 3000 molecules revealed 4 promising compounds that had no effect on the normal receptor.

In addition to midostaurin and gilteritinib, the study also revealed 2 more promising molecules. One of these molecules, EMI1, acts against the mutant EGFR by targeting the receptor for degradation with the help of other molecular machineries. The researchers noted that the more complex mechanism of action of EMI1 will make it more difficult for tumors to develop resistance to it.

The research team is working to create an improved version of the EMI1 molecule so that its ability to shrink tumors can be evaluated in cancer models and eventually patients.

Reference
  1. Leukemia Drugs May Help Patients with Treatment-Resistant Lung Cancer [news release]. Toronto, ON. University of Toronto website. Published February 24, 2020. https://www.utoronto.ca/news/leukemia-drugs-may-help-patients-treatment-resistant-lung-cancer-u-t-researchers. Accessed February 26, 2020.