LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant 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 BRAF V600E CRC is treatment w...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12943-025-02311-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849712810025549824 |
|---|---|
| author | Christopher A. Ladaika Averi Chakraborty Ashiq Masood Galen Hostetter Joo Mi Yi Heather M. O’Hagan |
| author_facet | Christopher A. Ladaika Averi Chakraborty Ashiq Masood Galen Hostetter Joo Mi Yi Heather M. O’Hagan |
| author_sort | Christopher A. Ladaika |
| collection | DOAJ |
| description | 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 BRAF V600E 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 BRAF V600E 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 BRAF mutant 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 BRAF V600E 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 BRAF V600E 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. |
| format | Article |
| id | doaj-art-2b53f8171a404d36b5f787c3e55c072d |
| institution | DOAJ |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-2b53f8171a404d36b5f787c3e55c072d2025-08-20T03:14:09ZengBMCMolecular Cancer1476-45982025-04-0124111610.1186/s12943-025-02311-zLSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancerChristopher A. Ladaika0Averi Chakraborty1Ashiq Masood2Galen Hostetter3Joo Mi Yi4Heather M. O’Hagan5Genome, Cell, and Developmental Biology Graduate Program, Department of Biology, Indiana University BloomingtonMedical Sciences Program, Indiana University School of MedicineIndiana University Melvin and Bren Simon Comprehensive Cancer CenterPathology and Biorepository Core, Van Andel InstituteMedical Sciences Program, Indiana University School of MedicineMedical Sciences Program, Indiana University School of MedicineAbstract 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 BRAF V600E 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 BRAF V600E 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 BRAF mutant 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 BRAF V600E 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 BRAF V600E 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.https://doi.org/10.1186/s12943-025-02311-zColorectal cancerLineage plasticityNeuroendocrineLSD1BRAFEncorafenib |
| spellingShingle | Christopher A. Ladaika Averi Chakraborty Ashiq Masood Galen Hostetter Joo Mi Yi Heather M. O’Hagan LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer Molecular Cancer Colorectal cancer Lineage plasticity Neuroendocrine LSD1 BRAF Encorafenib |
| title | LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer |
| title_full | LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer |
| title_fullStr | LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer |
| title_full_unstemmed | LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer |
| title_short | LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer |
| title_sort | lsd1 inhibition attenuates targeted therapy induced lineage plasticity in braf mutant colorectal cancer |
| topic | Colorectal cancer Lineage plasticity Neuroendocrine LSD1 BRAF Encorafenib |
| url | https://doi.org/10.1186/s12943-025-02311-z |
| work_keys_str_mv | AT christopheraladaika lsd1inhibitionattenuatestargetedtherapyinducedlineageplasticityinbrafmutantcolorectalcancer AT averichakraborty lsd1inhibitionattenuatestargetedtherapyinducedlineageplasticityinbrafmutantcolorectalcancer AT ashiqmasood lsd1inhibitionattenuatestargetedtherapyinducedlineageplasticityinbrafmutantcolorectalcancer AT galenhostetter lsd1inhibitionattenuatestargetedtherapyinducedlineageplasticityinbrafmutantcolorectalcancer AT joomiyi lsd1inhibitionattenuatestargetedtherapyinducedlineageplasticityinbrafmutantcolorectalcancer AT heathermohagan lsd1inhibitionattenuatestargetedtherapyinducedlineageplasticityinbrafmutantcolorectalcancer |