Scientists find opening to treat drug-resistant lung cancer

Freya Preimesberger

A team of scientists, including researchers from UT Southwestern and UT MD Anderson Cancer Center, have found a vulnerability in a form of lung cancer previously thought to be untreatable. 

Selinexor, a previously developed drug also known as KPT-330, may be able to treat the disease and will undergo clinical trials in January. The researchers published their results in Nature on Sept. 28. 

In many forms of cancer, a potentially cancer-causing gene called KRAS is mutated and causes cells to proliferate. Scientists had previously found the structure of KRAS-mutant lung cancer, which comprises 30 percent of all lung cancers, made it difficult to develop treatments for patients.

“From a structural point of view, [KRAS] is molecularly a little ball, meaning that it doesn’t have clefts where a compound can fit,” said Pier Scaglioni, associate professor of internal medicine at UT Southwestern and co-author of the study. “Traditionally, it’s structurally not conducive to being targeted — this has been deemed the reason why it’s considered undruggable.”

Around one in 15 people in the U.S. will be diagnosed with lung cancer in their lifetime, and about 1 in 4 cancer deaths are from lung cancer, according to the American Cancer Society. The pharmaceutical industry and small labs alike have struggled to find effective treatments, Scaglioni said.

The research team found, by inactivating the protein XPO1, many KRAS-mutant cells died in lab-grown lung cancer cultures and in mice with lung cancer. XPO1 is located in nuclear membranes and plays an important role in exporting proteins and RNA from the nucleus. Normally, XPO1 responds to signals from outside of the cell, but mutations in KRAS can cause it to stop responding to external signals, leading cells to proliferate. 

Fortunately, a drug capable of inhibiting XPO1 already existed.

“Because of advances in drug design, there are many times compounds [are] already designed to inhibit certain proteins,” Scaglioni said. “In this case, we were lucky in the sense that there is a drug called selinexor that actually binds to XPO1 and inhibits it.”

Selinexor was developed by Karyopharm Therapeutics for other cancer types and is currently undergoing clinical trials for leukemia, lymphoma and myeloma.

The researchers conducted trials on mice in which 83 percent of those with KRAS-mutant lung cancer responded to treatment with selinexor. According to the study, the remaining cases were found to be treatable after adding a second drug that suppresses the gene YAP1, which is responsible for proteins involved in cell death. 

XPO1 inhibitors are a promising treatment for many patients with lung cancer, according to the study.

The researchers will begin clinical trials for the use of selinexor on KRAS-mutant lung cancer at UT Southwestern. The trials will be led by David Gerber, associate professor of internal medicine.

“Now that we know it’s actually effective and the drug is already in clinical trials for other types of cancer, we will do clinical trials in January for KRAS-mutant lung cancer,” Scaglioni said. “We have a very strong infrastructure to study lung cancer; there are other investigators [who] are important in making this study possible.”