When a person with lung cancer stops responding to a particular drug treatment, one possible reason is the cancer has morphed into a different subtype that is no longer sensitive to that drug.
This phenomenon, known as lineage plasticity, is responsible for about 15% of cases of drug resistance in people with lung adenocarcinoma (LUAD) that has a mutation in the gene EGFR and is being treated with an EGFR inhibitor. As a result of this lineage plasticity, LUAD transforms into small cell lung cancer (SCLC), which is much more aggressive.
Understanding the biology of this identity switching is a top priority for lung cancer researchers at Memorial Sloan Kettering.
“The million-dollar question is: Can we find a way to block the switch so the cancer can’t evade the drugs designed to kill it?” says Triparna Sen, a cancer biologist in the Sloan Kettering Institute.
In a new study, published June 21, 2021, in Cancer Discovery, Dr. Sen and her colleagues reported results that take scientists closer to that goal. They identified a suite of molecular changes that accompany lineage plasticity as lung cancers morph from one subtype into another.
A Powerful Collaboration
To make these discoveries, the team took advantage of the close collaboration between physicians and researchers at MSK. One member of the team, physician-scientist Charles Rudin, the Sylvia Hassenfeld Chair in Lung Cancer Research, helped obtain lung cancer tumors from patients. From these, the scientists were able to identify tumors that had both pre-transformation LUAD and post-transformation SCLC areas, tumors that had fully undergone lineage switching, and tumors that had not. They separated the LUAD and SCLC sections from these samples and performed a battery of measurements to assess changes at the molecular level. The paper’s first author, Alvaro Quintanal-Villalonga, a postdoc in the Rudin lab, then worked with MSK scientists Richard Koch and Brian Loomis to analyze these data.
The results were revealing. Certain genetic changes, they found, were commonly associated with lineage switching. For example, loss of function of two genes, RB1 and TP53, was seen in almost all samples that had undergone lineage switching, implying that these changes are key requirements. But while these changes appear necessary for the switch, they are not sufficient to actually cause it to happen.
More significant for driving the switch, they discovered, was a variety of changes in gene expression — genes turning on or off. These gene expression changes were not the result of mutations in DNA. Rather, they were caused by reversible alterations in DNA methylation, a type of epigenetic modification. As a result of these changes, the tumors become more like SCLC.
Blocking the Switch
With this list of the defining molecular changes between subtypes identified, the researchers next wanted to know if targeting any of these changes with drugs could prevent the switch and slow the growth of tumors.
To test this hypothesis, they made what’s called a xenograft model. They took a slice of a tumor from a patient and grew it in a mouse. Then they tested several drugs against it. The drug that had the most effect was an AKT inhibitor called samotolisib; AKT is one of the genes whose expression changes during lineage switching. The researchers speculate that AKT inhibitors might usefully be added to treatment regimens for people with certain lung cancers.
“The research points toward AKT inhibitors as potentially beneficial for patients whose lung cancer has transformed to SCLC, particularly tumors in which AKT signaling may be playing an important role,” Dr. Sen says. “The exciting thing is that AKT inhibitors are already FDA approved for use in people.”
But before this is tried in patients, more work needs to be done to see if the results hold up in other preclinical studies. If so, the findings could have broad applicability. Lineage plasticity-dependent drug resistance is also known to occur in prostate cancer, for example. Dr. Sen and her colleagues are eager to explore the implications of these findings with other researchers at MSK.
“We have asked a lot of questions in this study and answered a few,” Dr. Sen says. “But I think there is still much more to be done in this field.”
- Lung cancer can sometimes become resistant to drugs by changing its identity, called lineage plasticity.
- MSK researchers studied patient tumors with sensitive technologies to determine the changes in genes, gene expression, and other factors that underlie lineage plasticity.
- Some of the changes they uncovered are potentially targetable with drugs.
