Health
New insights into drug resistance in small cell lung cancer
Both families of Myc reverse switch to drug resistance
Two scientists from McPherson’s lab collaborated to conduct the research. Former graduate student Dr. Eli Grunblatt and postdoctoral researcher Dr. Nan Wu first examined the role of Myc’s family MYCN. They used genetic techniques to increase the amount of MYCN in a mouse model of small cell lung cancer. Excessive MYCN caused the tumor to develop faster and reduced the number of immune cells inside it to fight cancer. The dose of chemotherapy that caused regression of tumors with normal MYCN levels did not affect the growth of tumors with high MYCN.
Grunblatt and MacPherson confirmed these results in a patient-derived xenograft or PDX model. These models use tumor tissue taken from a patient and grown in mice. They genetically engineered chemosensitive tumor samples to express high levels of one of two different Myc family members, MYCN and MYCL. Again, the expression of one of the Myc family members reversed the biological switch. Untreated tumors melted in response to chemotherapy, but tumors containing any Myc family member did not.
This is the first example for researchers to genetically engineer tumor tissue in a PDX model to understand how different genes contribute to the chemotherapeutic response in physiological environments, according to McPherson.
Find MYCN Vulnerabilities
Cancer-causing mutations often provide tumor cells with growth and survival benefits over normal cells, but they can also create new vulnerabilities. To see if MYCN creates this Achilles tendon, Grunblatt and another student in the lab, Justin Norton, used CRISPR-based genetic tools to generate large amounts of MYCN.
Researchers have discovered that a gene (called USP7) that helps MYCN bypass the cell’s normal protein recycling system appears to be key to its ability to promote drug resistance.
Grunblatt treated tumors with high levels of MYCN with small molecules that blocked USP7 activity.
“If we don’t just give chemotherapy, [to the mice]”But I also give a USP7 inhibitor that causes the tumor to dissolve,” McPherson said. “So, by lowering Myc-N levels, we were able to resensitize chemotherapy-resistant tumors to chemotherapy.”
Further exploring the biology of small cell lung cancer
The findings suggest that blocking USP7, or other molecules that help MYCN to promote drug resistance, has therapeutic potential, McPherson said. RAPT Therapeutics, the company that provided the drug that Granblatt tested, is currently exploring the possibility of bringing it to the clinic.
Meanwhile, MacPherson’s lab is expanding its PDX model-based strategy of testing gene effects on tumors in more physiological contexts. It helps them better understand how different genes alter the biology of small cell tumors, which may help show new treatments, he said. They are also testing the potential role of hundreds of different genes in drug resistance.
“The goal is to identify the vulnerabilities associated with them. [cancer] McPherson said. “And we will develop a pipeline that reverses chemoresistance in a driver-specific way.”
This study was funded by the National Institutes of Health and the National Cancer Institute.
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