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Volume 9, Issue 5 (Suppl) J Cancer Sci Ther, an open access journal
ISSN: 1948-5956 Cancer Stem Cells and Oncology Research 2017
June 26-28, 2017
Page 55
10th International Conference on
June 26-28, 2017 London, UK
CANCER STEM CELLS AND
ONCOLOGY RESEARCH
The activation of RAF/MEK/ERK kinase cascade by variable β3-αC loop deletions triggers oncogenesis
Hu Jiancheng1,2, Yuan Jimin1,2, Ng Wan Hwa1,2 and Yap Jia Jun1,2
1National Cancer Centre Singapore, Singapore
2Duke-NUS Medical School, Singapore
RAF/MEK/ERK kinase cascade has well-defined role in cancer development. Aberrant activation of this kinase by genetic alterations
exists in >40% human cancers, which functions as a driver to trigger cancer pathogenesis. In current study, we identified a new
catalogue of mutations in RAF and MEK with variable deletions of β3-αC loop. These mutants are constitutively active and highly
oncogenic in vitro and in vivo. To develop strategies for targeting these mutants-driven cancers, we tested whether they were sensitive
to RAF/MEK inhibitors that used for clinic treatment of BRAF (V600E)-harboring cancers or undergoing clinic trials, and found that
all of them exhibit a strong drug resistance at cellular level and in tumor-xenograft mouse model. To explore molecular mechanism
that underlies this phenomenia, we next carried out a serial of biochemistry and structral analysis and demonstrated that β3-αC
loop deletions stimulate the homo-oligomerization of both RAF and MEK, which not only triggers their kinase activity but also
dramatically decreases their drug affinity. Together, our study provides a solid evidence that RAF and MEK mutants with β3-αC loop
deletions function as a cancer driver and a clear molecular basis that β3-αC loop deletions activate RAF and MEK and lead to strong
inhbitor resistance, and appeals a development of new inhibitors.
Biography
Hu Jiancheng received his PhD from University of Colorado Denver in 2007 and then Post-doctoral training at Washington University in St. Louis and Howard
Hughes Medical Institute. Since 2014, he has joined National Cancer Centre Singapore where he has served as the Principal Investigator at the Laboratory of
Cancer Signaling. He has published more than 15 papers in international renowned journals. His research interests include: (1) the regulatory mechanism of RAF
kinase and other oncogenic protein kinases under normal/pathological conditions; (2) molecular basis that underlie intrinsic and acquired resistance of kinase
inhibitors in clinic treatment of cancers; (3) the development of novel kinase inhibitors.
Hu Jiancheng et al., J Cancer Sci Ther 2017, 9:5(Suppl)
DOI: 10.4172/1948-5956-C1-102