Scientists Learn More about How Lung Cancer Becomes Resistant to Drugs

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MSK cancer biologist Triparna Sen

MSK cancer biologist Triparna Sen

For people with lung cancer, drug resistance is the major cause of relapse. A tumor might respond very well at first — maybe even shrinking down to an undetectable level — only to develop resistance and grow back.

Scientists are learning that one of the ways that lung cancers become resistant is through something called lineage plasticity. This means that lung cancer cells are essentially changing their identity so they are no longer dependent on the chemical process that the drug was designed to target.

In the case of lung cancer that is fueled by abnormal activity of the epidermal growth factor receptor (EGFR), which often treated with the targeted drug osimertinib (Tagrisso®), that means switching to a type of growth that bypasses EGFR.

Cancer biologist Triparna Sen, an Assistant Attending Biologist in the Thoracic Oncology Service in the Department of Medicine at MSK, and her colleagues are focused on trying to understand the drivers of these identity changes so that they can develop more effective therapies for people with lung cancer.

“We think this lineage plasticity depends on cells turning on or off different genetic and epigenetic programs,” Dr. Sen says. “But the specific genes that drive a particular transformation from one type of lung cancer into another are just now coming to light.”

MSK Scientists Reveal Biology of Shape-Shifting Lung Cancer
Lung cancer has an uncanny ability to change its identity to resist drugs. Researchers are learning what drives these changes.

In a study published in June 2021 in Cancer Discovery, Dr. Sen and her colleagues uncovered the molecular changes that underlie the transformation of lung adenocarcinoma into much more aggressive small cell lung cancer, which happens in about 15% of cases.

In their latest study, published October 16, 2021, in the Journal of Hematology and Oncology, Dr. Sen and her team focused on the switch from lung adenocarcinoma to squamous cell carcinoma, a much deadlier form of the disease. This switch occurs in about 7% to 9% of cases.

The scientists say their findings provide the first comprehensive molecular characterization of this transformation and identify potential ways to prevent or treat this mechanism of drug resistance in lung cancer.

Tackling the Problem from Multiple Angles

To make their discoveries, the team of researchers made use of tumor samples from patients being treated for lung cancer at MSK. Charles Rudin, who is Chief of the Thoracic Oncology Service at MSK, a joint member of the Molecular Pharmacology Program in the Sloan Kettering Institute, and a co-corresponding author on the paper, played a pivotal role in this regard. A portion of the samples were mixed-histology tumors, meaning that they contain two different types of cancer side by side — in this case, lung adenocarcinoma and squamous cell carcinoma. By surgically separating these types, the researchers could then compare them on a molecular level. (An open question at the outset was whether the squamous cell cancer cells in the tumor had originally been lung adenocarcinoma. The team determined an answer: yes.)

The paper’s first author, Alvaro Quintanal-Villalonga, a postdoc in the Rudin Lab, took the lead on characterizing the samples — understanding every little difference. He received crucial help from Natasha Rekhtman in the Department of Pathology, Richard Koche in the Center for Epigenetics Research, and Brian Houck-Loomis in the Center for Molecular Oncology, all at MSK. The scientists performed a battery of different tests on the samples, looking for histological, genetic, transcriptional, and epigenetic changes.

Overall, the changes pointed to transcriptional reprogramming (turning genes on or off) rather than genetic mutations (changes in DNA sequence) as the cause of the shift from adenocarcinoma to squamous cell carcinoma. Three genes seemed to be key: AKT, MYC, and EZH2, judging by the way their activity increased.

There's nothing better than finding a therapeutic option that can both prevent and reverse drug resistance.
Triparna Sen cancer biologist

At this point, all the scientists saw were correlations. To prove that these genes (mainly AKT and MYC) were acting as “drivers” of the transformation, they experimentally turned them on in a mouse model of human tumors and watched as the models became more squamous-like. This proved that these genes were indeed acting as drivers.

Next, they tested a drug targeting EZH2 in a mouse model of a human tumor. They found that this drug, when given along with the EGFR-targeting drug osimertinib, prevented the tumor from converting into a squamous cell tumor. Even more dramatic, the EZH2 inhibitor alone could resensitize the squamous-like tumors to osimertinib.

“There’s nothing better than finding a therapeutic option that can both prevent and reverse drug resistance,” Dr. Sen says.

While these results must still be confirmed, they point to EZH2 inhibitors — drugs that are already being tested in clinical trials in several different types of cancer — as a potential treatment option for patients whose tumors are at risk for this type of lineage plasticity or have already made the switch.

 

Key Takeaways
  • Drug resistance is a common problem in lung cancer.
  • Lung cancers can develop resistance to drugs through lineage plasticity: changing their identity so they are no longer dependent on the drug target.
  • Up to 9% of lung adenocarcinomas treated with an EGFR-targeting drug transform into squamous cell carcinoma, a deadlier form of the disease.
  • By blocking the genes involved in this change in mouse models, MSK researchers can prevent it from happening, and even undo it. 

This study was supported by the National Cancer Institute (R01 CA197936, U24 CA213274), the SU2C/VAI Epigenetics Dream Team, the Druckenmiller Center for Lung Cancer Research, the Parker Institute for Cancer Immunotherapy, the International Association for the Study of Lung Cancer, the National Institutes of Health (NIH K08 CA-248723), the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. Dr. Quintanal-Villalonga reports honoraria from AstraZeneca. Dr. Rudin has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Astra Zeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jazz, Lilly, Pfizer, PharmaMar, Syros, and Vavotek. Dr. Rudin also serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. Drs. Quintanal-Villalonga and Rudin are included on a US patent application related to this work.