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SUMMARY:“Map plasticity and synthetic lethality in oncogenic PI3K signal
 s with T cell leukemia” - Dr Jeroen Roose\; Dept of Anatomy\, University
  of California\, San Francisco
DTSTART:20170606T120000Z
DTEND:20170606T130000Z
UID:TALK71511@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:Ras GTPases are activated by RasGEFs (guanine nucleotide excha
 nge factors). GTPaseimpairing\nsomatic mutations in RAS genes\, such as KR
 ASG12D\, are among the most common\noncogenic events in metastatic cancer.
  In 2013\, we described a cancer Ras-signal driven by\noverexpression of t
 he RasGEF RasGRP1 in pediatric T-cell acute lymphoblastic leukemia (TALL)\
 npatients and murine models 1. We next established that RasGRP1 overexpres
 sion results\nin a constitutively high GTP-loading rate of Ras\, which is 
 constantly counterbalanced by\nhydrolysis of RasGTP 2. In KRASG12D T-ALLs 
 Ras does not rapidly cycle\, instead it is trapped in\nthe GTP-bound state
 . Thus\, there are at least two biochemically distinct leukemogenic Ras\ns
 ignals 3. There are no effective K-\, N-Ras\, or RasGRP1 inhibitors to dat
 e and blocking\noncogenic Ras signaling in the clinic remains a highly des
 ired goal.\n\nThe Ras-PI3K signaling pathway is tumor-promoting in many ty
 pes of cancer and has also been\ngenetically linked to ~50% of T-ALL patie
 nts. Patterns of PI3K activation are not uniform in TALL\ncell lines and l
 imited patient analyses. We utilized T-ALL as platform in combination with
 \nPI3K and mTOR inhibitors and high-throughput phospho-flow to systematica
 lly map PI3K\nsignals in KRASG12D and RasGRP1-overexpressing T-ALLs\, reve
 aling heterogeneity and\nplasticity 4. Secondly\, we utilized T-ALL as pla
 tform for fully saturated synthetic lethal screens\nwith the pan-PI3K inhi
 bitor GDC-0941 in combination with a high-complexity\, barcoded shRNA\nlib
 rary with up to 30 shRNA’s per single target 5. Results from these two d
 irections that include\nanalyses of combination therapy with 10 small mole
 cule inhibitors\, analysis of combination\ntherapy in different cancer typ
 es\, and in in vivo T-ALL preclinical mouse trials will be discussed.
LOCATION:Babraham - The Brian Heap Seminar Room
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