Study Probes Role of Epigenetics in Precision Medicine for Lung Cancer

New modeling could help explain why some patients develop resistance to tyrosine kinase inhibitors.

A new report could point the way toward improved precision therapy for patients with epidermal growth factor receptor (EGFR)-driven lung cancers.

The study, published in the journal Advanced Science, is based on computer modeling that suggests how different mutations may be linked with specific drug susceptibilities. The authors believe it could demonstrate how epigenetics can be used to help select precision treatment options.

Corresponding author Christine F. Brainson, PhD, of the University of Kentucky, and colleagues explained that while there are theories about the cellular origins of certain types of lung cancers, most cancers’ cellular origins remain unclear.

“Determining common lung tumor origins may help us to understand how to prevent malignant transformation and guide us to using appropriate therapeutics,” the authors wrote.

In the meantime, a number of precision medications are already on the market for patients with lung cancer, most of which use biomarkers in order to determine the best therapeutic approach.

“Biomarkers encoded by genetic changes are currently the predominant tools for deciding precision medicine options,” Brainson and colleagues wrote. “However, epigenetic biomarkers, including markers of cell states, could add crucial additional predictions of drug responses.”

In patients with EGFR-driven cancers, one of the most prominent classes of therapeutic options is tyrosine kinase inhibitors (TKIs). However, many patients have developed resistance to both first- and second-generation TKIs, prompting the development of new, third-generation TKIs, such as osimertinib (Tagrisso) and rociletinib. Yet, the authors noted that some patients have acquired resistance even to osimertinib, suggesting a need to better identify which patients are most likely to succeed (or not) on the drug.

In an effort to better understand EGFR-driven cancers, the investigators created a model that developed tumors of distinct epigenetic states using three-dimensional organotypic cultures.

“We discovered that EGFR mutation led to lung cancer with alveolar or bronchiolar features, which can originate from [alveolar type 2; AT2] cells or [brochioalveolar stem cells; BASC], but not basal cells or club cells of the trachea,” they explained.

Furthermore, they found that the clones they developed could “retain their epigenetic differences through passaging orthotopically in mice and crucially that they had distinct drug vulnerabilities that can be modulated through drug combinations.”

The findings could have implications for treatment decisions, as the investigators found that bronchiolar and alveolar tumors responded differently to therapy.

“Especially, the third generation TKI osimertinib and rociletinib targeting T790M gatekeeper mutation were both more effective in the AT2-derived alveolar tumoroids than the BASC-derived bronchiolar tumoroids,” they wrote.

Brainson and colleagues said it may be that bronchiolar and alveolar cells have different compositions of EGFR homo- and heterodimers, leading to different sensitivities to TKIs.

“Gene expression suggests that EGFR is less expressed in bronchiolar organoids; however, the EGFR signaling pathway was more enriched in the bronchiolar tumoroids than the alveolar ones,” they wrote. “Therefore, the bronchiolar cells might require higher doses of osimertinib and rociletinib to achieve the same level of EGFR repression.”

They added that it could also be related to the SOX2+ nature of the bronchiolar organoids, since existing evidence has suggested that the gene may be tied to osimertinib resistance.

The authors said more investigation is warranted before these findings can be translated into clinical decisions.


Chen F, Liu J, Flight RM, et al. Cellular origins of EGFR-driven lung cancer cells determine sensitivity to therapy. Adv Sci (Weinh). 2021;e2101999. doi:10.1002/advs.202101999

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