Dataset Information

LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAFV600E colorectal cancer

ABSTRACT: Background: BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis in part due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic BRAFV600E CRC is treatment with BRAF and EGFR inhibitors and recent FDA approval was given to use these inhibitors in combination with chemotherapy for patients with treatment naïve metastatic BRAFV600E CRC. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types. Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present in BRAFV600E CRC as compared to BRAF wildtype CRC. Methods: BRAF plus EGFR inhibitor treatment induced changes in cell composition were determined by gene expression, imaging and single cell approaches in multiple models of BRAF mutant CRC. Furthermore, multiple clinically relevant inhibitors of the lysine demethylase LSD1 were tested to determine which inhibitor blocked the changes in cell composition. Results: Combined BRAF and EGFR inhibition enriched for EECs in all BRAF mutant CRC models tested. Additionally, EECs and other secretory cell types were enriched in a subset of BRAFV600E CRC patient samples following targeted therapy. Importantly, inhibition of LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3. Conclusions: Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAFV600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs. Additionally, our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE290028 | GEO | 2025/04/30

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.

Dataset Information

LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAFV600E colorectal cancer

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets