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Identification of cells exhibiting elevated ERBB network activity in KRas/ Myc-driven lung tumours

ABSTRACT: Identification of cells exhibiting elevated ERBB network activity in KRas/ Myc-driven lung tumours

PROVIDER: PRJNA1322415 | ENA |

REPOSITORIES: ENA

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Identification of cells exhibiting elevated ERBB network activity in KRas/ Myc-driven lung tumours

Project description:Our lab has identified a completely unexpected requirement for ERBB signalling in KRAS‐driven Lung Adenocarcinoma (LuAd). We have shown that this requirement is present from the very outset of lung tumour initiation, and, crucially, we have found a pronounced increase in ERBB signalling during progression from low grade adenocarcinoma to locally invasive disease. We hypothesize that this increased activity, which manifests as strongly elevated expression of multiple EGF/ERBB-family ligands, such as Amphiregulin (AREG), and paracrine activation of ERBB2 on infiltrating macrophages, may be exploited for early detection of KRAS‐ driven malignancy. Alongside a more general increase in AREG expression as tumours progress to higher grade disease, we find individual cells that express extremely high levels of AREG mRNA. We refer to these cells as AREG super-expressers and their lineage identity is unknown. Cell morphology suggests they maybe epithelial, however, unlike the bulk of tumours, these cells fail to express the lung epithelial marker SPC and staining for cytokeratins is inconclusive. Their detection at and adjacent to the tumour:normal interface suggests that they maybe disseminating tumour cells undergoing EMT. Alternatively, they may belong to another lung-resident or infiltrating population, induced to express AREG through direct contact with tumour cells. Immediately adjacent to progressing tumours we find large numbers of F4/80-positive macrophages that stain strongly for tyrosine phosphorylated ERBB2 (p-Tyr-ERBB2), suggesting paracrine activation in response to local production of ERBB ligands. The aim of this part of the work is to identify the cell lineage of the AREG superexpressers and to investigate the effect of ERBB-inhibition using the multi-ERBB inhibitor Neratinib.

2025-09-15 | GSE307621 | GEO

Pan-ERBB inhibitors synergize with KRAS inhibitors in rectal cancer

Project description:Background: Emerging RAS inhibitors show promise in treating KRAS-mutated malignancies, but resistance mechanisms limit their clinical efficacy. Given recent clinical findings associating KRAS mutations with reduced response to neoadjuvant therapy in rectal cancer (RC), we aimed to investigate their impact on treatment outcomes and explore potential therapeutic strategies. Methods: We conducted a retrospective analysis of 390 RC patients to evaluate the association of KRAS mutations with disease-free survival (DFS) and response to therapy. We assessed the efficacy of KRAS inhibitors in RC cell lines, patient-derived organoids (PDOs), and patient-derived cell lines (PDCLs), and explored adaptive resistance mechanisms through transcriptomic profiling and unbiased drug screening experiments. Results: Mutant KRAS was associated with a reduced DFS and RCs harboring G12C and G12V mutations had less complete pathological responses. KRAS-mutated RC cells demonstrated adaptive resistance to KRAS inhibitors, characterized by transcriptomic restoration of oncogenic pathways, including MYC and E2F and upregulation of ERBB2/3 gene expression. Consistently, drug screening identified EGFR family inhibitors as potent combinatorial partners, effectively overcoming KRAS inhibitor tolerance by inducing apoptosis. In patient-derived models, the novel pan-RAS inhibitor RMC-6236 combined with EGFR inhibitors demonstrated significant synergistic effects and prevented long-term tumor outgrowth. Conclusion: Our findings highlight the negative impact of KRAS mutations, particularly G12C and G12V, on RC treatment outcomes. Adaptive resistance by transcriptomic upregulation of ERBB genes limits the efficacy of KRAS inhibitors. Combining these with pan-ERBB inhibitors enhances anti-tumor effects in patient-derived cellular RC models showing its potential as alternative to the combination with anti-EGFR antibodies.

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RNA-seq to investigate impact of treatment of KRAS mutant A549 lung adenocarcinoma cells with the multi-ERBB inhibitor Neratinib

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RNA-seq to investigate impact of treatment of KRAS mutant NCI-H358 lung adenocarcinoma cells with the multi-ERBB inhibitor Neratinib

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Pan-ERBB inhibitors synergize with KRAS inhibitors in rectal cancer

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Progression of KRas^G12D;Rosa26-MYC tumours to invasive disease

Project description:The aim of the study was to investigate gene expression tumour progression of KRas*/MYC driven lung tumours from adenocarcinoma in situ to invasive disease.

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