November 6, 2023, NEW YORK – About 20 to 25% of cancers involve mutations in a protein complex called SWI/SNF. Yet drugs designed to block SWI/SNF activity haven’t always worked as expected. Researchers led by Ludwig Harvard’s Karen Adelman have now figured out why: they report in the current issue of Cell that when drugs block SWI/SNF activity, a second molecule steps up to compensate.
Blocking this second molecule along with SWI/SNF suppressed cancer cell growth in lab dishes, suggesting that a similar two-drug approach could make treatments more effective in people.
“I am excited about this work because it shows an alternative path forward for treating cancers in which the SWI/SNF complex is mutated,” said Adelman, who is the Edward S. Harkness Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at Harvard Medical School.
In human cells, DNA gets tightly packed with proteins into a form called chromatin that resembles a string of pearls. Molecules called chromatin remodelers unspool chromatin in different spots, exposing certain genes so they can be used before they’re packed away again.
SWI/SNF is one such chromatin remodeler. SWI/SNF treatments are supposed to suppress cancer-driving gene activity by stopping the mutated complex from providing inappropriate access to genes.
But Adelman and her colleagues discovered that blocking SWI/SNF suppresses the activity of only a subset of genes. Another molecule, EP400, kicks in to restore access to genes. Only by blocking both SWI/SNF and EP400 could the researchers successfully suppress abnormal gene activity.
The two-punch treatment worked in eight patient cell lines representing four kinds of cancer: acute myeloid leukemia, diffuse intrinsic pontine glioma (DIPG), prostate cancer and non-small cell lung cancer. Some of these cell lines had mutations in SWI/SNF, others did not.
“Part of the strength of the study is that the one-two punch can be used even in cancer cells with normal SWI/SNF,” said Adelman.
The full HMS media release from which this summary is derived can be found here.