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Systematic Functional Annotation of Somatic Mutations in Cancer
Ng, Patrick Kwok-Shing,Li, Jun,Jeong, Kang Jin,Shao, Shan,Chen, Hu,Tsang, Yiu Huen,Sengupta, Sohini,Wang, Zixing,Bhavana, Venkata Hemanjani,Tran, Richard,Soewito, Stephanie,Minussi, Darlan Conterno,Mo Cell Press 2018 CANCER CELL Vol. No.
<P><B>Summary</B></P> <P>The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Developed a versatile functional genomic platform for somatic mutation annotation </LI> <LI> Annotated >1,000 genomic aberrations, doubling the number of known driver mutations </LI> <LI> Assessed performance of existing algorithms for mutation functional predictions </LI> <LI> Built a user-friendly, open-access data portal for community-based investigation </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations
Zhang, Yiqun,Kwok-Shing Ng, Patrick,Kucherlapati, Melanie,Chen, Fengju,Liu, Yuexin,Tsang, Yiu Huen,de Velasco, Guillermo,Jeong, Kang Jin,Akbani, Rehan,Hadjipanayis, Angela,Pantazi, Angeliki,Bristow, C Elsevier Science B.V., Amsterdam 2017 CANCER CELL Vol.31 No.6
Wang, Chao,Gu, Chao,Jeong, Kang Jin,Zhang, Dong,Guo, Wei,Lu, Yiling,Ju, Zhenlin,Panupinthu, Nattapon,Yang, Ji Yeon,Gagea, Mihai (Mike),Ng, Patrick Kwok Shing,Zhang, Fan,Mills, Gordon B. American Association for Cancer Research 2017 Cancer Research Vol.77 No.7
<P>Interactions between HIPPO, YAP/TAZ, and the PI3K/AKT pathway may be therapeutically targetable, providing new approaches to treating endometrial cancers and other cancers where the HIPPO pathway is a core oncogenic driver.</P><P>The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor–induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growth <I>in vivo</I>. In addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer. <I>Cancer Res; 77(7); 1637–48. ©2017 AACR</I>.</P>
Comprehensive Characterization of Cancer Driver Genes and Mutations
Bailey, Matthew H.,Tokheim, Collin,Porta-Pardo, Eduard,Sengupta, Sohini,Bertrand, Denis,Weerasinghe, Amila,Colaprico, Antonio,Wendl, Michael C.,Kim, Jaegil,Reardon, Brendan,Kwok-Shing Ng, Patrick,Jeon Elsevier 2018 Cell Vol.174 No.4
Sun, Chaoyang,Fang, Yong,Yin, Jun,Chen, Jian,Ju, Zhenlin,Zhang, Dong,Chen, Xiaohua,Vellano, Christopher P.,Jeong, Kang Jin,Ng, Patrick Kwok-Shing,Eterovic, Agda Karina B.,Bhola, Neil H.,Lu, Yiling,Wes American Association for the Advancement of Scienc 2017 Science translational medicine Vol.9 No.392
<P>Mutant <I>RAS</I> has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple <I>RAS</I> mutant tumor models across tumor lineages where <I>RAS</I> mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of <I>BRCA1/2</I> and <I>p53</I> mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in <I>RAS</I> mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor–induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant <I>RAS</I> to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in <I>RAS</I> mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with <I>RAS</I> mutant tumors where there are few effective therapeutic options.</P>