| Popis: |
Lung cancer is still the leading cause of cancer-related deaths, and although important therapy advancements have been achieved, ~1.6 million people die from lung cancer annually. Non-small cell lung cancer (NSCLC), which makes up ~85% of lung cancer cases, is mainly treated with radiotherapy, chemotherapies, and targeted agents. Targeted agents are selected based on the mutation spectrum of the tumor. In NSCLC the epidermal growth factor receptor (EGFR) is commonly mutated and, leads to increased proliferation and cell survival. The standard-of-care treatment for patients with activating mutations in EGFR is treatment with tyrosine kinase inhibitors (TKI), such as erlotinib. While tumors initially respond to TKIs, most patients develop resistance after 1-2 years. In ~60% of TKI resistant tumors, resistance is the result of a secondary mutation in EGFR, whereas, in the remaining 20%, tumors turn on bypass track-signals to overcome inhibition of the EGFR pathway. In the remaining 15-20% of the cases the mechanisms underlying resistance are unknown. Most studies focus on the gain of function of oncogenes as mediators of resistance; however, little is known about the role that tumor suppressors play in TKI resistance. Hence, we performed a genome-wide CRISPR Cas9 knock-out screen to identify genes that when knocked-out would drive erlotinib resistance. Fold enrichment analysis of sgRNAs, identified KMT5C as a top candidate. KMT5C is a histone methyltransferase that trimethylates H4K20 (H4K20me3), enabling the establishment of constitutive and facultative heterochromatin. The process by which KMT5C is reduced in tumors is unknown, yet data from human samples suggests that the KMT5C transcript is globally downregulated in NSCLC and in tumor samples resistant to the third-generation TKI osimertinib. Additionally, loss of the modification made by KMT5C (H4K20me3), influences the prognosis of NSCLC, indicating that loss of KMT5C function is a crucial mechanism in carcinogenesis. We recently described how loss of KMT5C leads to increased transcription of the oncogene MET, due to a loss in H4K20me3-mediated repression of a long non-coding RNA transcription (LINC01510) upstream of MET. This mechanism was found to be responsible for driving TKI resistance in EGFR mutant cells. Historically, KMT5C has been associated with generation of constitutive heterochromatin (cHC); however, recent reports, including our own, indicate that KMT5C also regulates transcription in regions outside of cHC. Our preliminary evidence suggests that deposition of H42K0me3 via KMT5C in regions outside of cHC, is less stable than in cHC regions. This novel finding led us to hypothesize that regulation of KMT5C and H42K0me3 at different regions of heterochromatin is a dynamic process, and future work will aim at understanding this process and its relevance in cancer progression and TKI resistance. Citation Format: Alejandra Agredo, Arpita Pal, Jihye Son, Nadia A. Lanman, Andrea L. Kasinski. Loss of the methyltransferase KMT5C drives resistance to tyrosine kinase inhibitors via H4K20me3 regulation in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4752. |
