CRISPR/Cas9 untuk Canonical Mutations pada Kanker Pankreas: Harapan Baru Terapi Presisi
DOI:
https://doi.org/10.36312/ej.v6i4.3594Keywords:
CRISPR/Cas9, Kanker Pankreas, Terapi Gen PresisiAbstract
Kanker pankreas, khususnya Pancreatic Ductal Adenocarcinoma (PDAC), merupakan salah satu jenis kanker dengan tingkat mortalitas tertinggi di dunia. Kompleksitas biologis dan diagnosis yang terlambat menyebabkan rendahnya angka harapan hidup pasien, bahkan setelah menjalani terapi konvensional. Secara genetik, PDAC ditandai oleh empat canonical mutations utama, yaitu pada gen KRAS, TP53, SMAD4, dan CDKN2A, yang secara kolektif membentuk molecular signature khas kanker pankreas. Mutasi pada gen-gen tersebut berperan penting dalam mengubah mekanisme regulasi seluler seperti proliferasi, apoptosis, dan diferensiasi, sehingga menjadi target potensial untuk terapi berbasis pengeditan gen. Teknologi CRISPR/Cas9, yang berasal dari sistem kekebalan bakteri, menawarkan kemampuan pengeditan gen dengan presisi tinggi melalui panduan RNA spesifik (sgRNA). Sistem ini memungkinkan inaktivasi (knockout), perbaikan mutasi (gene correction), maupun regulasi ekspresi gen. Berbagai penelitian praklinis menunjukkan bahwa penggunaan CRISPR/Cas9 dapat menekan aktivitas mutasi KRAS, memulihkan fungsi TP53, mengaktifkan kembali SMAD4, dan mengendalikan siklus sel melalui CDKN2A, yang secara keseluruhan menekan pertumbuhan serta metastasis sel kanker pankreas. Meski demikian, penerapan teknologi ini masih menghadapi tantangan, seperti efisiensi pengantaran ke jaringan pankreas, risiko efek off-target, dan heterogenitas tumor. Namun, dengan kemajuan dalam sistem penghantaran non-virus, varian Cas9 presisi tinggi, serta teknologi prime editing dan base editing, CRISPR/Cas9 menawarkan prospek besar sebagai dasar terapi presisi generasi baru bagi kanker pankreas. Artikel ini menyajikan sintesis komprehensif terhadap CRISPR/Cas9 pada empat canonical mutations PDAC yang belum banyak dirangkum secara sistematis dalam literatur terdahulu.
CRISPR/Cas9 for Canonical Mutations in Pancreatic Cancer: New Hope for Precision Therapy
Abstract
Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is one of the cancers with the highest mortality rates worldwide. Biological complexity and late diagnosis contribute to low survival rates, even after conventional therapy. Genetically, PDAC is characterized by four major canonical mutations: in the KRAS, TP53, SMAD4, and CDKN2A genes, which collectively form the molecular signature of pancreatic cancer. Mutations in these genes play a key role in altering cellular regulatory mechanisms such as proliferation, apoptosis, and differentiation, making them potential targets for gene-editing therapies. CRISPR/Cas9 technology, derived from the bacterial immune system, offers high-precision gene editing capabilities through specific guide RNA (sgRNA). This system enables inactivation (knockout), mutation repair (gene correction), and regulation of gene expression. Various preclinical studies have shown that CRISPR/Cas9 can suppress KRAS mutation activity, restore TP53 function, reactivate SMAD4, and control the cell cycle through CDKN2A, all of which ultimately suppress the growth and metastasis of pancreatic cancer cells. However, the application of this technology still faces challenges, such as delivery efficiency to pancreatic tissue, the risk of off-target effects, and tumor heterogeneity. However, with advances in non-viral delivery systems, high-precision Cas9 variants, and prime and base editing technologies, CRISPR/Cas9 offers great prospects as the basis for a new generation of precision therapies for pancreatic cancer.
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