Lung cancer, artwork
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Scientists have discovered the molecular events driving the conversion of EGFR-driven lung adenocarcinoma to an aggressive neuroendocrine cancer indistinguishable from small cell lung cancer (SCLC). For the first time, the team revealed that the Myc oncogene alone is capable of this type of histological transformation in SCLC. The discovery raises the possibility of learning more about potential new targets to intervene before lung adenocarcinoma transforms to the more deadly neuroendocrine SCLC type. Their findings are published in a paper in Science.

Treatments for lung adenocarcinoma primarily include targeted therapies against EGFR. However, the cancers often transform to the point where they no longer work. “It is thought that the cancer has become independent of that original driver pathway,” explains first author Eric Gardner, PhD, a fellow in the lab of Harold Varmus at Weill Cornell Medicine.

To understand more about the drivers of this transformation, the team generated mouse models to study the ‘before’ and ‘after’ states of alveolar type 2 cells—the precursors of lung adenocarcinoma cells—on their journey to alternate fates, including neuroendocrine SCLC.

“We wanted to study very carefully the minimal residual disease states to see the steps that happen over time in a way we could not with human tissues,” says Gardner. By following the expression of single oncogenes in different lung-cell lineages the team found that process of histological transformation is regulated by the tolerance of different cell types to different oncogenic drivers.

What Gardner and colleagues observed is that over time, a stem-cell state emerges depending on whether the RB1 tumor suppressor was lost or not. The loss of RB1 causes the tumor cells to rework their oncogenic driver from EGFR to the Myc oncogene, causing the cells to change to a small cell lung cancer. While most lung cells are resistant to transformation by Myc, neuroendocrine cells are highly sensitive to its oncogenic effects.

“This has not been shown before that neuroendocrine SCLC cancers are transformed by the Myc oncogene alone,” adds Gardner. Indeed, viewing the development of SCLC is notoriously difficult as it has not been known to have pre-malignant states like lung adenocarcinoma does. Because of this, studying its progression has been challenging in human tissues as the process is ignited quickly and progresses rapidly.

The animal model offered the ability to use a complicated genetically engineered model to see the effect of specific oncogenes on different types of cells in the lung and trace them fluorescently. In this way, the researchers could excise transforming cells and study them over time to see the changes.

While the team found that Myc is sufficient to drive the cells to a neuroendocrine lineage small cell lung cancer state, they knew that it is toxic to the alveolar lineage. “These things are not cross-compatible,” says Gardner, who explains why histological transformation is so profound because initial treatment will be quite toxic to the alveolar or adenocarcinoma cell and after some time, the driver flips to a new pathway. “There may be points in time where one could introduce an intervention that is required to make that next step,” he adds.

For example, a patient receiving an EGFR tyrosine kinase inhibitor may have a profound response. But based on their genotype where RB1 and p53 are lost, they are likely to undergo histological transformation. “That’s really the highest hazard ratio described, to my knowledge, where you almost know those patients are going to transform. The question is, can we then add something else on during the residual fate to prevent these alternative histologic transformations if we had very good therapeutics that could target Myc-dependent signaling.”

While there currently are no approved Myc-targeted therapies, candidates are in clinical trials.

While the researchers do not have a clearly defined target, the team plans to study the genetics of this histological transformation to SCLC. “I think that is going to pay dividends because now we have systems where we can finally follow these cells, understand how the immune system may keep them in check initially, and then lose control to better understand what the early targets could be in small cell, because that is still something where we have not made major improvements.”

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