Scientists find lethal vulnerability in treatment-resistant lung cancer

Researchers working in four labs at UT Southwestern Medical Center have found a chink in a so-called ‘un-druggable’ lung cancer’s armour – and located an existing drug that might provide a treatment.

The study describes how the drug Selinexor (KPT-330) killed lung cancer cells and shrank tumours in mice when used against cancers driven by the aggressive and difficult-to-treat KRAS cancer gene. Selinexor is already in clinical trials for treatment of other types of cancer, primarily leukaemia and lymphoma but also gynaecological, brain, prostate, and head and neck cancers.

Lung cancer is the No. 1 cancer killer in the U.S., responsible for more than 158,000 deaths a year, according to the National Cancer Institute (NCI), and the KRAS oncogene is believed to be responsible for about 25 percent of all lung cancer cases. The 5-year survival rate for lung cancer is below 18 percent.

Cancers caused by the KRAS mutation have been a target for researchers since the mutation was discovered in humans in 1982. But, due in part to this oncogene’s almost impervious spherical shape, no one was able to find an opening for attack, said Dr. Pier Scaglioni, Associate Professor of Internal Medicine at UT Southwestern and a contributing author to the study.

Dr. Michael A. White, Adjunct Professor of Cell Biology and senior author of the study, assembled multiple research teams and used robotic machines to create and sift through trays with thousands of cancer cell/potential drug combinations to uncover the KRAS mutation’s weakness.

The scientists found that targeting and inactivating the protein XPO1, found in the cell nucleus and used to transport gene products from the nucleus to the cytoplasm, killed most of the KRAS mutant cancer cells.

‘We found that inhibiting the XPO1 gene kills lung cancer cells that are dependent on KRAS,’ Dr. Scaglioni said. ‘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,’ added Dr. White, also a research executive at Pfizer Inc. ‘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, Selinexor, developed by Karyopharm Therapeutics, will be the focus of a multi-centre lung cancer clinical trial led by UT Southwestern’s Dr. David Gerber, Associate Professor of Internal Medicine. That trial is expected to open for enrolment next year.

UT Southwestern Medical Center