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

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

PROVIDER: PRJEB24899 | ENA |

REPOSITORIES: ENA

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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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¬The EGFR/ErbB inhibitor neratinib promotes apoptosis and clearance by airway macrophages

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Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN a melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAF and MEK1/2 in PTEN null, BRAFV600Ecells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with BRAFi/MEKi identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600Ecells. The findings indicate that PTEN null BRAFV600E melanoma exhibits increased reliance on ERBB/HER signaling when treated with clinically approved BRAFi/MEKi combinations. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

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E-MTAB-6483

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

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