Loss of KMT5C Promotes EGFR Inhibitor Resistance in NSCLC via LINC01510-Mediated Upregulation of MET

Abstract

EGFR inhibitors (EGFRi) are standard-of-care treatments administered to patients with non–small cell lung cancer (NSCLC) that harbor EGFR alterations. However, development of resistance posttreatment remains a major challenge. Multiple mechanisms can promote survival of EGFRi-treated NSCLC cells, including secondary mutations in EGFR and activation of bypass tracks that circumvent the requirement for EGFR signaling. Nevertheless, the mechanisms involved in bypass signaling activation are understudied and require further elucidation. In this study, we identify that loss of an epigenetic factor, lysine methyltransferase 5C (KMT5C), drives resistance of NSCLC to multiple EGFRis, including erlotinib, gefitinib, afatinib, and osimertinib. KMT5C catalyzed trimethylation of histone H4 lysine 20 (H4K20), a modification required for gene repression and maintenance of heterochromatin. Loss of KMT5C led to upregulation of an oncogenic long noncoding RNA, LINC01510, that promoted transcription of the oncogene MET, a component of a major bypass mechanism involved in EGFRi resistance. These findings underscore the loss of KMT5C as a critical event in driving EGFRi resistance by promoting a LINC01510/MET axis, providing mechanistic insights that could help improve NSCLC treatment. Significance: Dysregulation of the epigenetic modifier KMT5C can drive MET-mediated EGFRi resistance, implicating KMT5C loss as a putative biomarker of resistance and H4K20 methylation as a potential target in EGFRi-resistant lung cancer.

Analysis of Gene Expression Heterogeneity Reveals Therapeutic Targets and Novel Regulators of Metastasis

“…KMT5C tri-methylates H4K20Me3 and acts as an epigenetic repressor ( 27 ). However, its role in breast cancer progression has not been addressed, and there are conflicting reports for other cancer types ( 28–30 ). To test whether KMT5C regulates metastasis, we generated TNBC cells with stable over-expression of KMT5C and confirmed the increased tri-methylation at histone H4K20 (Figs.…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…Additionally, deletion of lysine methyltransferase 5 C (KMT5C), an HMT responsible for histone H4 lysine 20 trimethylation (H4K20me3), upregulates lncRNA-LINC01510 and promotes MET transcription, leading to EGFR-TKI resistance in NSCLC through activation of the bypass pathway. 415 SET and MYND domain containing 2 (SMYD2) are highly expressed in ccRCC, and associated with multidrug resistance, including sunitinib in RCC. Mechanistically, SMYD2 binds to the promoter of miR-125b, inhibiting the expression of Dickkopf WNT signaling pathway inhibitor 3 (DKK3) and promoting proliferation and migration.…”

Emerging Role of Noncoding RNAs in EGFR TKI-Resistant Lung Cancer

“…The hepatocyte growth factor (HGF) receptor, also known as MET, has been shown to be activated by miR-205/ERRFI1 and LINC01510. Thus, the PI3K/AKT pathway is enhanced, causing resistance to gefitinib, afatinib, erlotinib and osimertinib [ 49 , 50 ]. In a similar manner, ncRNAs such as miR-223, lncRNA GAS5 and hsa_circ_0005576 regulate IGF1R expression and subsequently influence the resistance of lung cancer cells to EGFR TKIs [ 32 , 51 , 52 , 53 ].…”

“…By directly targeting MET, miRNAs such as miR-1-3p and miR-206 attenuate gefitinib resistance by inactivating the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways [ 63 ]. In contrast, lncRNA LINC01510 promotes MET expression to maintain EGFR TKI resistance [ 50 ]. Moreover, emerging research has indicated that circBFAR functionally promotes the MET pathway by sponging miR-34b-5p [ 64 ], which can be hypothesized to cause EGFR TKI resistance.…”