Publications by authors named "M F Gjerstorff"
Background: Despite promising preclinical studies, the application of DNA methyltransferase inhibitors in treating patients with solid cancers has thus far produced only modest outcomes. The presence of intratumoral heterogeneity in response to DNA methyltransferase inhibitors could significantly influence clinical efficacy, yet our understanding of the single-cell response to these drugs in solid tumors remains very limited.
Methods: In this study, we used cancer/testis antigen genes as a model for methylation-dependent gene expression to examine the activity of DNA methyltransferase inhibitors and their potential synergistic effect with histone deacetylase inhibitors at the single-cancer cell level.
Cancer/testis antigens (CTAs) are widely expressed in melanoma and lung cancer, emerging as promising targets for vaccination strategies and T-cell-based therapies in these malignancies. Despite recognizing the essential impact of intratumoral heterogeneity on clinical responses to immunotherapy, our understanding of intratumoral heterogeneity in CTA expression has remained limited. We employed single-cell mRNA sequencing to delineate the CTA expression profiles of cancer cells in clinically derived melanoma and lung cancer samples.
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- Resistance to MAPK inhibitors in melanoma is linked to lower levels of the tumor suppressor AMBRA1, which predicts poor treatment response.
- Loss of AMBRA1 triggers phenotype changes and leads to a resistance mechanism that bypasses the usual pathways, increasing reliance on FAK1.
- Combining MAPK inhibitors with FAK1 inhibitors can effectively prevent resistance in melanomas that have low AMBRA1 expression, highlighting AMBRA1's potential as a predictive marker for treatment efficacy.