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Cho, Sung-Yup,Chae, Jeesoo,Na, Deukchae,Kang, Wonyoung,Lee, Ahra,Min, Seoyeon,Kang, Jinjoo,Choi, Boram,Lee, Jieun,Sung, Chang Ohk,Chuang, Jeffrey H.,Lee, Charles,Lee, Won-Suk,Park, Hansoo,Kim, Jong-Il American Association for Cancer Research 2019 Clinical Cancer Research Vol.25 No.9
<P><B>Purpose:</B></P><P>Genomic and transcriptomic alterations during metastasis are considered to affect clinical outcome of colorectal cancers, but detailed clinical implications of metastatic alterations are not fully uncovered. We aimed to investigate the effect of metastatic evolution on <I>in vivo</I> treatment outcome, and identify genomic and transcriptomic alterations associated with drug responsiveness.</P><P><B>Experimental Design:</B></P><P>We developed and analyzed patient-derived xenograft (PDX) models from 35 patients with colorectal cancer including 5 patients with multiple organ metastases (MOMs). We performed whole-exome, DNA methylation, and RNA sequencing for patient and PDX tumors. With samples from patients with MOMs, we conducted phylogenetic and subclonal analysis and <I>in vivo</I> drug efficacy test on the corresponding PDX models.</P><P><B>Results:</B></P><P>Phylogenetic analysis using mutation, expression, and DNA methylation data in patients with MOMs showed that mutational alterations were closely connected with transcriptomic and epigenomic changes during the tumor evolution. Subclonal analysis revealed that initial primary tumors with larger number of subclones exhibited more dynamic changes in subclonal architecture according to metastasis, and loco-regional and distant metastases occurred in a parallel or independent fashion. The PDX models from MOMs demonstrated therapeutic heterogeneity for targeted treatment, due to subclonal acquisition of additional mutations or transcriptomic activation of bypass signaling pathway during tumor evolution.</P><P><B>Conclusions:</B></P><P>This study demonstrated <I>in vivo</I> therapeutic heterogeneity of colorectal cancers using PDX models, and suggests that acquired subclonal alterations in mutations or gene expression profiles during tumor metastatic processes can be associated with the development of drug resistance and therapeutic heterogeneity of colorectal cancers.</P>
Cho, Sung-Yup,Han, Jee Yun,Na, Deukchae,Kang, Wonyoung,Lee, Ahra,Kim, Jooyoung,Lee, Jieun,Min, Seoyeon,Kang, Jinjoo,Chae, Jeesoo,Kim, Jong-Il,Park, Hansoo,Lee, Won-Suk,Lee, Charles American Association for Cancer Research 2017 Molecular cancer therapeutics Vol.16 No.10
<P>Colorectal cancer is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature, and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups have been limited. KRAS and BRAF mutations are prevalent genetic alterations in colorectal cancers, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments. In this study, we have found that a subgroup of colorectal cancers, defined by having either KRAS or BRAF (KRAS/BRAF) mutations and BCL2L1 (encoding BCLXL) amplification, can be effectively targeted by simultaneous inhibition of BCL-XL (with ABT-263) and MCL1 (with YM155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect in vitro as well as in in vivo patient-derived xenograft models. Our data suggest that combined inhibition of BCL-XL and MCL1 provides a promising treatment strategy for this genomically defined colorectal cancer subgroup. (C) 2017 AACR.</P>
Cho, Sung-Yup,Sung, Chang Ohk,Chae, Jeesoo,Lee, Jieun,Na, Deukchae,Kang, Wonyoung,Kang, Jinjoo,Min, Seoyeon,Lee, Ahra,Kwak, Eunhye,Kim, Jooyoung,Choi, Boram,Kim, Hyunsoo,Chuang, Jeffrey H.,Pak, Hyo-Ky American Society of Hematology 2018 Blood Vol.131 No.17
<P>Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV1-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV1-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV1-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV1-DLBLs revealed enrichment ofmutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumorgrowth inEBV1-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.</P>
Park, Hansoo,Cho, Sung-Yup,Kim, Hyerim,Na, Deukchae,Han, Jee Yun,Chae, Jeesoo,Park, Changho,Park, Ok-Kyoung,Min, Seoyeon,Kang, Jinjoo,Choi, Boram,Min, Jimin,Kwon, Jee Young,Suh, Yun-Suhk,Kong, Seong-H National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.40
<P><B>Significance</B></P><P>Gastric cancer (GC) is one of the major causes of cancer-related deaths worldwide, but targeted therapy for GC is limited. Here, we identified two druggable targets from genomic alteration profiling of 103 patients with GC from Asia and validated the target suitability using patient-derived GC xenograft models, which recapitulate the tumor biology observed in patients. Combination therapy of irinotecan (standard treatment) with a <I>BCL2L1</I> (<I>BCL2</I>-like 1)-targeted drug was effective in size reduction of GC tumors having amplification of the <I>BCL2L1</I> gene, and genomic mutations of deleted in liver cancer 1 (<I>DLC1</I>) were associated with increased sensitivity to a ROCK inhibitor. Therefore, our study strongly suggests that <I>BCL2L1</I> and <I>DLC1</I> can serve as targets for novel GC therapies.</P><P>Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [<I>APC</I>, <I>CTNNB1</I>, and <I>DLC1</I> (deleted in liver cancer 1)], ErbB signaling (<I>ERBB2</I>, <I>PIK3CA</I>, and <I>KRAS</I>), and p53 signaling/apoptosis [<I>TP53</I> and <I>BCL2L1</I> (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene <I>BCL2L1</I> was observed, and subsequently a <I>BCL2L1</I> inhibitor was shown to markedly decrease cell viability in <I>BCL2L1</I>-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in <I>DLC1</I> were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates <I>BCL2L1</I> and <I>DLC1</I> as potential druggable targets for specific subsets of GC cases.</P>