New small cell lung cancer model reveals critical role of two mutated genes


Small cell lung cancer (SCLC) develops mostly in smokers and is so aggressive it almost always becomes resistant to chemotherapy and radiation. The disease is widely believed to originate from pulmonary neuroendocrine cells (PNECs), but they have proven difficult to generate in the lab, making it challenging for oncology researchers to study SCLC and find new therapies.

Researchers from Weill Cornell Medicine in New York have figured out how to grow PNECs from human embryonic stem cells—and in so doing they’ve gained new insight into two genes that are commonly mutated in SCLC. They believe their new model of the disease will be useful for fine-tuning treatments at various stages of tumor development.

The Weill Cornell team, which was co-led by Nobel Prize winner and former National Cancer Institute director Harold Varmus, M.D., started by differentiating embryonic stem cells into lung progenitor cells. Then they created PNECs by blocking the NOTCH cell-signaling pathway, according to a statement.  

From there, they zeroed in on two tumor-suppressing genes that are frequently mutated in SCLC. When they blocked NOTCH and RB, the lung progenitors formed even more PNECs than they did when the team blocked NOTCH alone. When they also inhibited TP53, the PNECs both promoted cell proliferation and prevented cell death. When the cells were injected under the skin of mice, tumors began to grow. The team reported its findings in the Journal of Experimental Medicine.

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The Weill Cornell researchers believe their human cell-based model offers advantages over mouse models of SCLC that are traditionally used in research. “Since the SCLC-like tumors grown subcutaneously in immunodeficient mice appear to have low tumor potency (slow-growing and noninvasive), it is likely that this system will enable studies of tumor progression,” they wrote in their study.

The search for effective drugs to treat SCLC has been fraught with false starts and failures. In December, AbbVie pulled the plug on a phase 3 trial of Rova-T in advanced SCLC because overall survival rates were worse among patients taking the drug than they were in the control arm of the study. A couple of weeks later, Shares of G1 Therapeutics plummeted on news that its experimental drug, trilaciclib—which is designed to enhance immune function during chemotherapy—did not do better than a placebo in a SCLC trial.

Weill Cornell’s Varmus hopes the new model of SCLC that his team created will ultimately be able to be used to determine what causes early-stage SCLC tumors to develop into the aggressive cancers seen in people. “If so, it should be possible to test cells at different stages of tumor development for susceptibility and resistance to therapeutic strategies,” he said.