Researchers uncover lethal vulnerability in treatment-resistance lung cancer
A team from the University of Texas Southwestern (Dallas, TX, USA) have found a potential means by which to treat an ‘undruggable’ form of lung cancer, and have located an existing drug that could provide a treatment.
A team from the University of Texas Southwestern (Dallas, TX, USA) has found a chink in a so-called ‘undruggable’ lung cancer’s armor, and has identified an existing drug that could be a potential therapeutic. The study describes how a drug, KPT-330, killed lung cancer cells and shrank tumors in mice when used against cancers driven by the KRAS cancer gene. KPT-330 is already in clinical trials for treatment of other cancers, primarily leukemia and lymphoma.
Lung cancer is the number one cause of cancer-related deaths in the US, and the KRAS oncogene is believed to be responsible for about 25% of all lung cancer cases. Cancers caused by the KRAS mutation have been a target for researchers since the mutation was discovered in humans. However, due in part to the genes spherical shape, researchers have struggled to find an opening for attack.
The team assembled multiple research teams and employed robotic machines to create and sift through trays with thousands of cancer cell/potential drug combinations, with the goal of uncovering the KRAS mutation’s weakness.
The scientists found that targeting and inactivating the protein XPO1 killed most of the KRAS mutant cancer cells. “We found that inhibiting the XPO1 gene kills lung cancer cells that are dependent on KRAS,” explained contributing author Pier Scaglioni. “The unexpected coincidence here is that there is an existing drug that will inhibit XPO1.”
“We know that this drug hits the XPO1 target in people,” explained Michael White, senior author of the study. “But we will not know whether the drug will be effective until clinical trials are done, which should be completed in about two years.”
Based on the results of this study, KPI-330 will be the focus of a multicenter lung cancer clinical trial. In preclinical results from cancer cells and mouse models, 83% of the KRAS mutant lung cancers responded to KPI-330, and the remaining 17% of lung cancers could be killed by adding a second drug to inhibit YAP1, which is known to be involved in the promotion of several other cancers. The team also found an existing drug, verteporfin, which could be effective in blocking YAP1.
Kim J, McMillan E, Kim HS et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature, doi:10.1038/nature19771 (2016) (EPub ahead of print); www.utsouthwestern.edu/newsroom/news-releases/year-2016/september/kras-cancer-white.html