A newly diagnosed patient with advanced-stage adenocarcinoma, a sub-type of non-small cell lung cancer (NSCLC), may have their biopsy tissue tested for known biomarkers. The oncologist requests biomarker testing to look for changes in cancer cells to help personalize the patient’s treatment. Patients that are positive for biomarkers such as PD-L1 and EGFR have seen a lot of progress in treatment options over the last five years. However, targeted treatments for the KRAS mutation haven’t yet arrived.
The KRAS protein is critical in promoting cell growth and survival in non-cancerous cells. In KRAS-positive lung cancer cells, the KRAS protein is mutated to be always “on.” This causes the mutated KRAS protein to activate many pathways that cause the cell to divide and grow uncontrollably.
Approximately 25% of lung adenocarcinoma patients are positive for a mutation in the KRAS gene. They are given platinum-based treatments, such as cisplatin, that have been effective in extending survival time for many KRAS-positive lung cancer patients.
Frank Slack, PhD, Director of the Institute for RNA Medicine at Beth Israel Deaconess Medical Center in Boston and a recipient of a 2013 LUNGevity research grant award, is studying approaches on how to target KRAS-positive lung cancer.
“When the link between lung cancer and the KRAS gene was first discovered, scientists were hopeful that they finally had a way to stop KRAS-positive lung cancer. By inhibiting KRAS, researchers expected to inhibit tumor growth,” explains Dr. Slack. “Unfortunately, KRAS is so important to normal cellular function that scientists’ initial attempts to stop KRAS didn’t work. The therapies were extremely toxic to patients. KRAS turned out to be a very tricky target.”
Dr. Slack’s laboratory studies microRNAs, or tiny molecules that bind to DNA and regulate the amounts of protein in the cell. He made the exciting discovery of a microRNA that reduces the amount of KRAS protein in cells.
With the help of a 2013 LUNGevity Foundation research grant, Dr. Slack continued this research to test how microRNAs could contribute to regulating the amount of mutated KRAS in the cell. He is now seeking federal funding to conduct a clinical trial to test these microRNAs as lung cancer therapeutics for patients with KRAS-positive lung cancer.
The LUNGevity funding also allowed Dr. Slack to study the DNA code near the KRAS gene. Through those studies, he found genetic variations in the sites where the microRNA binds to the DNA and affects the quantity of the protein in the cell. Dr. Slack thinks these genetic variations could predispose someone to developing KRAS-positive lung cancer.
“The evidence is good, but it still needs to be proven conclusively,” notes Dr. Slack. “If things go as we hope, we will be able to test for these variants and identify patients who are at increased risk for KRAS-positive lung cancer. We could begin screening patients regularly and catch the cancer early when it is the most treatable.”
There are other promising avenues for the treatment of KRAS-positive lung cancer. One approach is to screen large batches of small chemicals to identify molecules that selectively bind to specific varieties of mutated KRAS proteins. These small molecule treatments are already in clinical trials, and the results of the trials should be available soon. If the results are favorable, some subsets of patients with KRAS-positive lung cancer may have another avenue of treatment become available in the near future.
In addition, some scientists are attempting to reduce toxicity by using therapies that don’t directly block KRAS function, but instead block the pathways that KRAS activates. Studies have shown that when a single pathway is blocked, other pathways compensate for the blockage. Therefore, researchers are now looking for combinations of therapies that can work downstream of KRAS cooperatively to inhibit tumor growth with minimal toxicity to the patient.
“The scientific community has recognized how important this is. All the research won’t turn out the way we would like it to, but there are a lot of smart people working on this,” says Dr. Slack. “Patients can continue to help by enrolling in clinical trials and providing tissue and blood samples. Working together, I know we will find better outcomes for KRAS-positive lung cancer patients.”
Dr. Basu Roy is LUNGevity's Director of Translational Research Programs/Director of Patient FoRCe.