2. Academic Validation
  3. LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer

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

  • Mol Cancer. 2025 Apr 23;24(1):122. doi: 10.1186/s12943-025-02311-z.
Christopher A Ladaika 1 2 3,  Averi Chakraborty 2 4,  Ashiq Masood 3 5,  Galen Hostetter 6,  Joo Mi Yi 2 7 8,  Heather M O'Hagan 9 10 11 12
Affiliations

Affiliations

  • 1 Genome, Cell, and Developmental Biology Graduate Program, Department of Biology, Indiana University Bloomington, Bloomington, IN, 47405, USA.
  • 2 Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, 47405, USA.
  • 3 Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA.
  • 4 Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, IN, 47405, USA.
  • 5 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
  • 6 Pathology and Biorepository Core, Van Andel Institute, Grand Rapids, MI, 49503, USA.
  • 7 Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, South Korea.
  • 8 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
  • 9 Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, 47405, USA. hmohagan@iu.edu.
  • 10 Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA. hmohagan@iu.edu.
  • 11 Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, IN, 47405, USA. hmohagan@iu.edu.
  • 12 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. hmohagan@iu.edu.
PMID: 40264166 DOI: 10.1186/s12943-025-02311-z
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 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 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.

Keywords

BRAF; Cetuximab; Colorectal cancer; Encorafenib; LSD1; Lineage plasticity; Neuroendocrine.

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