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Novel syngeneic cell lines for studying high-risk BRAFV600E-driven colorectal cancer in vivo [RNA-seq_NaJa]

ABSTRACT: Combining anti-EGFR antibodies with BRAF/MEK/ERK-pathway blockade opened new treatment options for BRAFV600E driven colorectal cancer (CRC). Nevertheless, responses of these poor-prognostic cancers are short-lived and heterogeneous, thereby highlighting the unmet need for novel concepts integrating targeted therapy and immuno-oncology. To this end, an immunocompetent mouse model with reliable disease onset and responding to clinically relevant drugs is essential but unavailable. Here, we generated three cell lines from peritoneal metastases originating from orthotopically transplanted organoids carrying BRAFV600E, Trp53R172H and Apc mutations and characterized their ground state and responses to targeted therapy compounds in detail by RNAseq, WES and various functional assays. Interestingly, these NaJa lines displayed distinct differentiation states and responses to the clinically relevant RAF inhibitors (RAFi) encorafenib and exarafenib, thereby resembling the clinical heterogeneity of BRAFV600E driven CRC. RAFi resistance was overcome by the EGFR-family inhibitor afatinib. RAFi also influenced the expression of the antigen presentation machinery, cytokines and other immunomodulatory factors. Upon re-transplantation into syngeneic mice, all NaJa lines established aggressive tumors with distinct tumor microenvironments correlated with their differentiation states. Thus, the NaJa lines provide a unique tool to study tumor heterogeneity, drug resistance and the interplay between tumor, stroma and immune cells in BRAFV600E driven CRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE296998 | GEO | 2026/01/13

REPOSITORIES: GEO

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Similar Datasets

Novel syngeneic cell lines for studying high-risk BRAFV600E-driven colorectal cancer in vivo [RNA-seq_organoids]

Project description:Combining anti-EGFR antibodies with BRAF/MEK/ERK-pathway blockade opened new treatment options for BRAFV600E driven colorectal cancer (CRC). Nevertheless, responses of these poor-prognostic cancers are short-lived and heterogeneous, thereby highlighting the unmet need for novel concepts integrating targeted therapy and immuno-oncology. To this end, an immunocompetent mouse model with reliable disease onset and responding to clinically relevant drugs is essential but unavailable. Here, we generated three cell lines from peritoneal metastases originating from orthotopically transplanted organoids carrying BRAFV600E, Trp53R172H and Apc mutations and characterized their ground state and responses to targeted therapy compounds in detail by RNAseq, WES and various functional assays. Interestingly, these NaJa lines displayed distinct differentiation states and responses to the clinically relevant RAF inhibitors (RAFi) encorafenib and exarafenib, thereby resembling the clinical heterogeneity of BRAFV600E driven CRC. RAFi resistance was overcome by the EGFR-family inhibitor afatinib. RAFi also influenced the expression of the antigen presentation machinery, cytokines and other immunomodulatory factors. Upon re-transplantation into syngeneic mice, all NaJa lines established aggressive tumors with distinct tumor microenvironments correlated with their differentiation states. Thus, the NaJa lines provide a unique tool to study tumor heterogeneity, drug resistance and the interplay between tumor, stroma and immune cells in BRAFV600E driven CRC.

2026-01-13 | GSE296999 | GEO

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

Project description: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.

2025-04-30 | GSE290028 | GEO

Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable, BRAFV600E metastatic colorectal cancer [dataset 1]

Project description:The BRAF inhibitor encorafenib and anti-EGFR antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAFV600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAFwild-type CRC. In this phase I/II study (NCT04017650) of 26 participants with MSS BRAFV600E mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval (CI) 29-71) and median progression-free survival of 7.4 months (95% CI, 5.6-9.6). Transcriptomic profiling of pretreatment biopsies and extracellular vesicle RNA (evRNA) isolated from plasma show enrichment of non-canonical MAP kinase signaling and immune activation signatures for responders. Complement pathway activation enriches in non-responder biopsies. On serial evRNA profiling, decreased MAPK signature and increased interferon gamma response signature associate with sustained treatment benefit. MSS BRAFV600E mCRC with baseline MAP kinase activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.

2025-07-21 | GSE302921 | GEO

Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable, BRAFV600E metastatic colorectal cancer [dataset 2]

2025-07-21 | GSE302922 | GEO

Proteomic and phosphoproteomic analyses for HT-29

Project description:Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and run into a bottleneck in the current treatment strategies. To identify regulatory pathways independent of the MAPK pathway in BRAFV600E CRC, we performed CRISPR-Cas9 screening, and and find targeting glutathione peroxidase 4 (GPX4) remarkably overcome BRAF inhibitor (BRAFi) ± epidermal growth factor receptor (EGFR) inhibitor (EGFRi) resistance in BRAFV600E CRC. Specifically, BRAFi ± EGFRi induced GPX4 upregulated expression and antagonized ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promoted PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265, which induce GPX4 expression. Targeting PLK1 promoted BRAFi ± EGFRi inhibition and triggered ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a novel PLK1–CBX8–GPX4 signaling axis relaying the ferroptosis mechanism of therapeutic resistance operated independent of MAPK signaling and suggest a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC.

2025-02-28 | PXD058218 | Pride

Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer [HT29 samples]

Project description:Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated by a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.

2024-11-06 | GSE269881 | GEO

Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer [RKO samples]

2024-11-06 | GSE269880 | GEO

Synthetic lethal combinations targeting PLK1-CBX8-GPX4 axis with BRAF and EGFR inhibition in BRAF V600E colorectal cancer

2024-11-25 | PXD058213 |

Cell specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells

Project description:Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient or tumor specific variations, we constructed cell line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting ppERK and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

2024-09-03 | PXD047912 | Pride

Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis

Project description:Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and represents a therapeutic bottleneck. To identify resistance mechanisms of the mitogen-activated protein kinase (MAPK) pathway in BRAFV600E CRC, we perform genome-wide CRISPR-Cas9 screening and discover that targeting glutathione peroxidase 4 (GPX4) overcomes resistance to BRAF inhibitor (BRAFi) combined with or without epidermal growth factor receptor inhibitor (EGFRi) in BRAFV600E CRC. Specifically, BRAFi ± EGFRi upregulates GPX4 expression, which antagonizes therapy-induced ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promotes PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265 to drives GPX4 expression. Targeting PLK1 enhances BRAFi ± EGFRi inhibition and triggers ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a PLK1–CBX8–GPX4 signaling axis that relays the ferroptosis mechanism of therapeutic resistance and propose a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC.

2025-02-28 | GSE283185 | GEO

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