Precision targeting tumor cells using cancer-specific InDel mutations with CRISPR-Cas9
Taejoon Kwon, Jae Sun, Soyoung Lee, In‐Joon Baek, Keon Woo Khim, Eun A Lee, Eun Kyung Song, Daniyar Otarbayev, Woojae Jung, Yong Hwan Park, Minwoo Wie, Juyoung Bae, Himchan Cheng, Jun Hong Park, Namwoo Kim, Yuri Seo, Seongmin Yun, Ha Eun Kim, Hyo Eun Moon, Sun Ha Paek, Tae Joo Park, Young Un Park, Hwanseok Rhee, Jang Hyun Choi, Seung Woo Cho, Kyungjae Myung
Abstract
An ideal cancer therapeutic strategy involves the selective killing of cancer cells without affecting the surrounding normal cells. However, researchers have failed to develop such methods for achieving selective cancer cell death because of shared features between cancerous and normal cells. In this study, we have developed a therapeutic strategy called the cancer-specific insertions-deletions (InDels) attacker (CINDELA) to selectively induce cancer cell death using the CRISPR-Cas system. CINDELA utilizes a previously unexplored idea of introducing CRISPR-mediated DNA double-strand breaks (DSBs) in a cancer-specific fashion to facilitate specific cell death. In particular, CINDELA targets multiple InDels with CRISPR-Cas9 to produce many DNA DSBs that result in cancer-specific cell death. As a proof of concept, we demonstrate here that CINDELA selectively kills human cancer cell lines, xenograft human tumors in mice, patient-derived glioblastoma, and lung patient-driven xenograft tumors without affecting healthy human cells or altering mouse growth.