Silencing Epigenetic Complexes Re-sensitizes Drug-Resistant Cancer Cells

Researchers studying lung cancer cell lines found that chromatin remodeling underlies one type of osimertinib resistance.

| 4 min read
A doctor reaches out to touch a lung tumor, highlighted in red.

Lung cancers often become resistant to targeted drug therapies. Researchers discovered a way to overcome one type of epigenetic resistance.

© iStock, Mohammed Haneefa Nizamudeen

Register for free to listen to this article
Listen with Speechify
0:00
4:00
Share
A doctor reaches out to touch a lung tumor, highlighted in red.
Lung cancers often become resistant to targeted drug therapies. Researchers discovered a way to overcome one type of epigenetic resistance.

Targeted anti-cancer therapies dramatically improve patient outcomes in EGFR-mutant lung adenocarcinomas,1 but many tumors acquire resistance to these drugs over time. Because there are numerous ways in which cancers become resistant to therapies, scientists often do not know why particular tumors stop responding or how to re-sensitize them.

“This is a big unmet need in the field because in order to really get to the next step in the treatment of the disease, we need to understand these mechanisms of resistance,” said Katerina Politi, a cancer biologist at the Yale School of Medicine.

Politi and Cigall Kadoch, a cancer biologist at the Dana-Farber Cancer Institute and Harvard Medical School, recently published a paper in Cancer Cell addressing this question.2 Their research teams, led by co-first authors Fernando de Miguel and Claudia Gentile, wanted to understand the resistance mechanisms to the targeted tyrosine kinase inhibitor (TKI) osimertinib, which treats EGFR-mutant tumors. Osimertinib is a first-line therapy for this type of cancer, and resistance almost always develops.3

To explore this resistance, the researchers used five different EGFR-mutant lung cancer cell lines, all of which were sensitive to TKIs. To generate osimertinib-resistant versions of these cell lines, they exposed each to the drug, selected those that survived the treatment, and analyzed their exomes.

Politi and her team tried to find additional mutations in the EGFR gene responsible for the osimertinib resistance and came up empty-handed. As a result, the researchers postulated that an epigenetic mechanism that affected whether or not particular genes could be transcribed may be the culprit. They performed RNA sequencing to look at differences in gene expression between resistant and sensitive lung cancer cells and found many differentially up- and down-regulated genes.

Next, the researchers performed Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq), which looks at chromatin accessibility. They found that resistant cells had differentially-accessible genomic regions, and that more than 50 percent of gene expression changes corresponded with DNA accessibility changes at or near gene promoters or enhancers. When they examined these gene targets, the researchers found various genes and pathways modulated in the resistant state, such as upregulation of the EMT and RTK signaling pathways and downregulation of epithelial cell differentiation and cell-cell adhesion. These changes could lead to resistance by altering the cell’s dependence on the original oncogene, changing signaling, or modulating apoptosis. The researchers concluded that chromatin accessibility changes for key gene regulatory programs underlie the difference between parental and TKI-resistant EGFR-mutant cancer cell lines, and that epigenetic factors are likely to be playing a key role in resistance.

Microscopy image of <em >EGFR</em>-mutant patient-derived cancer cells
These EGFR-mutant patient-derived cancer cells are resistant to osimertinib when injected into mice.
Fernando de Miguel

During these experiments, the researchers became particularly interested in the SMARCA4 protein, a key component of the chromatin remodeling complex mSWI/SNF. Using epigenome analysis, the researchers found that mSWI/SNF complexes were located at different sites across the genome in TKI-resistant lung cancer cell lines versus drug-sensitive cell lines. The presence or absence of mSWI/SNF altered chromatin accessibility and changed certain transcriptional programs.

To see if the cells could become re-sensitized to osimertinib, Politi, Kadoch, and their teams used short hairpin RNA to knock down SMARCA4 in the resistant cell lines. They also knocked out the gene in human EGFR-mutant, TKI-resistant tumors that had been implanted in mice. In yet another experiment, they used a drug to pharmacologically suppress SMARCA4’s activity in resistant cell lines. The researchers found that a subset of these resistant cancer models were re-sensitized to osimertinib.

“We think that the shift in chromatin accessibility that SMARCA4 and mSWI/SNF mediates in the resistant setting allows the cells to survive better, to proliferate and divide better, and also withstand the stresses that are imposed by drugs, by activating an antioxidant response in the cells,” said Politi. SMARCA4 knock-down in the presence of osimertinib elevated the levels of reactive oxygen species, which would help lead to their demise.

See also “Epigenetic Marks May Cause Brain Tumor Formation

Finally, in mice harboring osimertinib-resistant, patient-derived xenografts of EGFR-mutant lung cancer, the researchers inhibited mSWI/SNF ATPase activity with a drug called FHD-286. When combined with osimertinib, this treatment slowed tumor growth. FHD-286 is currently in clinical development as a cancer therapeutic by Foghorn Therapeutics, co-founded by Kadoch.

“The pharmaceutical industry is very interested in targeting [SMARCA4],” said Mark Rubin, a prostate cancer researcher at the University of Bern who was not involved in this study. However, such drugs are often toxic because they affect both tumor and healthy cells. “This study provides a rationale for further developing these drugs to sensitize resistant cells. Epigenetic therapies are very important, and the challenge is how to bring them into the clinic,” said Rubin.

Keywords

Meet the Author

  • Rachael Moeller Gorman

    Rachael freelances for both scientific and lay publications, and loves telling the stories behind the science.
Share
You might also be interested in...
Loading Next Article...
You might also be interested in...
Loading Next Article...
3D illustration of a gold lipid nanoparticle with pink nucleic acid inside of it. Purple and teal spikes stick out from the lipid bilayer representing polyethylene glycol.
February 2025, Issue 1

A Nanoparticle Delivery System for Gene Therapy

A reimagined lipid vehicle for nucleic acids could overcome the limitations of current vectors.

View this Issue
Enhancing Therapeutic Antibody Discovery with Cross-Platform Workflows

Enhancing Therapeutic Antibody Discovery with Cross-Platform Workflows

sartorius logo
Considerations for Cell-Based Assays in Immuno-Oncology Research

Considerations for Cell-Based Assays in Immuno-Oncology Research

Lonza
An illustration of animal and tree silhouettes.

From Water Bears to Grizzly Bears: Unusual Animal Models

Taconic Biosciences
Sex Differences in Neurological Research

Sex Differences in Neurological Research

bit.bio logo

Products

Photo of a researcher overseeing large scale production processes in a laboratory.

Scaling Lentiviral Vector Manufacturing for Optimal Productivity

Thermo Fisher Logo
Collage-style urban graphic of wastewater surveillance and treatment

Putting Pathogens to the Test with Wastewater Surveillance

An illustration of an mRNA molecule in front of a multicolored background.

Generating High-Quality mRNA for In Vivo Delivery with lipid nanoparticles

Thermo Fisher Logo
Tecan Logo

Tecan introduces Veya: bringing digital, scalable automation to labs worldwide