Lung Cancer Cells Switch Oncogenic Drivers

Lung adenocarcinoma (LUAD), the most common form of lung cancer, is already a challenging disease. It is currently the leading cause of cancer death in the United States.¹ In response to therapies that inhibit their genetic drivers, LUAD cells may undergo transformation as a mechanism of resistance and begin to exhibit traits of a more aggressive and difficult-to-treat cancer type known as small cell lung cancer (SCLC).

To gain deeper insight into the mechanisms underlying this problematic transition, Eric Gardner, a lung cancer biologist at Weill Cornell Medicine, and his colleagues developed mouse models that recapitulated the process. The researchers found that the lung cell type that gives rise to LUAD is typically unaffected by mutations in one of the oncogenes driving SCLC. However, when the team inhibited an oncogenic driver for LUAD and deleted specific tumor suppressor genes, a subset of LUAD cells converted into a stem-like state. Under these conditions, the cells were plastic enough to respond to the cancer gene driving the SCLC transformation, the team reported in Science.²

Gardner’s team first focused their efforts on the challenging task of creating mouse strains that could recapitulate the complex transformation in a simplified model. “It took three years to make these mice, and then it took another two to three years to actually model this process,” said Gardner.

The design of these genetically engineered mice was inspired by other mouse models for different lung cancer types. “I didn’t really develop anything that new so much as I took a little bit of this, a little bit of that, and brought it together,” he explained. The resulting mouse strains had mechanisms to turn on the expression of cancer genes involved in either LUAD or SCLC in specific cell types, for example.

Researchers also labelled the mouse tumor cells with a fluorescent protein to track their course and used single-cell RNA sequencing to characterize gene expression throughout the transformation.

The models revealed that lung alveolar epithelial cells that give rise to LUAD are sensitive to mutations in the oncogene coding for the epidermal growth factor receptor (EGFR), but are resistant to transformation driven by overexpression of Myc, one of the cancer genes leading to SCLC. Conversely, pulmonary neuroendocrine cells, the cells of origin for SCLC, are responsive to Myc overexpression, but not to EGFR mutations.

Gardner and his colleagues explored the mechanisms that rendered alveolar epithelial cells susceptible to the oncogenic effects of Myc. The researchers discovered that by deleting specific tumor suppressor genes—some previously linked to SCLC—and blocking EGFR function, a subset of the alveolar epithelial cells transformed into stem-like cells that are sensitive to both EGFR and Myc. This plasticity allowed these cells to transform into Myc-driven SCLC neuroendocrine tumor cells. “This represents . . . a fundamental switch in the oncogenic driver program,” said Gardner.

The advantage of this system is that it enables researchers to turn on and off the expression of lineage-specific oncogenic drivers, according to Hideo Watanabe, a genomic scientist studying lung cancer lineages at the Icahn School of Medicine at Mount Sinai who did not participate in this study. “It’s a very elegant [and] laborious way to look at this [transition],” he said.

Watanabe added that these mouse models may help scientists identify potential biomarkers activated during the transition from LUAD to SCLC, which could be monitored in patients to guide treatment decisions. However, he cautioned that researchers still need to determine how accurately the molecular processes in the model reflect LUAD to SCLC transformation in human lung cancer. Moreover, he noted, this might represent just one of many transition mechanisms, given the heterogeneity of lung cancer.

Watanabe believes that there's a long way to go before these findings have direct clinical implications. Yet, he added that the study offers foundational information that may help scientists develop future strategies for preventing this transformation in patients.