When a person with lung cancer stops responding to a particular drug treatment, one possible reason is that the cancer has turned 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 pulmonary adenocarcinoma (LUAD) which has a mutation in the gene. EGFR and is treated with an EGFR inhibitor. Due to this lineage plasticity, LUAD turns into small cell lung cancer (SCLC), which is much more aggressive.
Understanding the biology of this identity shift is a top priority for lung cancer researchers at Memorial Sloan Kettering.
âThe million dollar question is, can we find a way to block the switch so that cancer cannot escape drugs designed to kill it? Says Triparna Sen, cancer biologist at the Sloan Kettering Institute.
The million dollar question is, can we find a way to block the switch so that cancer cannot escape drugs designed to kill it?
In a new study, published on June 21, 2021, in Discovery of cancer, Dr. Sen and his colleagues reported results that bring scientists closer to this goal. They identified a series of molecular changes that accompany lineage plasticity as lung cancers transform from one subtype to another.
A powerful collaboration
To make these discoveries, the team took advantage of the close collaboration between doctors and researchers at MSK. A member of the team, physician-scientist Charles Rudin, Sylvia Hassenfeld Chair in Lung Cancer Research, helped secure lung cancer patients. From these, the scientists were able to identify tumors that had both pre-transformation LUAD areas and post-transformation SCLC areas, tumors that had completely undergone lineage change, and tumors that did not. had not done. They separated the LUAD and SCLC sections of these samples and performed a battery of measurements to assess changes at the molecular level. The first author of the article, Alvaro Quintanal-Villalonga, a post-doctoral fellow at the Rudin laboratory, then worked with MSK scientists Richard Koch and Brian Loomis to analyze this data.
The results were revealing. Certain genetic changes, they found, were generally associated with a lineage change. For example, the loss of function of two genes, RB1 and TP53, was observed in almost all samples that underwent a lineage change, implying that these changes are key requirements. But while these changes seem necessary for change, they are not enough to actually cause it.
More important to driving the switch, they found, 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 look more like a SCLC.
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With this list of defining molecular changes between the identified subtypes, the researchers then wanted to know if targeting any of these changes with drugs could prevent the change and slow tumor growth.
To test this hypothesis, they did what is called a xenograft model. They took a slice of tumor from a patient and cultured it in a mouse. Then they tested several drugs against her. The drug that worked the most was an AKT inhibitor called samotolisib; AKT is one of the genes whose expression changes when changing lineage. The researchers believe that AKT inhibitors could be usefully added to treatment regimens for people with certain lung cancers.
“Research indicates that AKT inhibitors may be beneficial for patients whose lung cancer has transformed into SCLC, particularly tumors in which AKT signaling may play an important role,” said Dr Sen. “What is exciting is that AKT inhibitors are already approved by the FDA for use in humans.”
But before it’s tried in patients, more work needs to be done to see if the results hold up in other preclinical studies. If so, the results could have wide applicability. Lineage plasticity dependent drug resistance is also known to occur in prostate cancer, for example. Dr Sen and his colleagues are eager to explore the implications of these findings with other researchers at MSK.
âWe asked a lot of questions in this study and answered a few,â says Dr. Sen. âBut I think there is still a lot to do in this area. “
Key points to remember
Lung cancer can sometimes become resistant to drugs by changing its identity, called lineage plasticity.
MSK researchers studied patients’ tumors with sensitive technologies to determine changes in genes, gene expression, and other factors that underlie lineage plasticity.
Some of the changes they discovered can be targeted with medication.
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