Map plasticity and synthetic lethality in oncogenic PI3K signals with T cell leukemia
Ras GTPases are activated by RasGEFs (guanine nucleotide exchange factors). GTPaseimpairing somatic mutations in RAS genes, such as KRASG12D, are among the most common oncogenic events in metastatic cancer. In 2013, we described a cancer Ras-signal driven by overexpression of the RasGEF RasGRP1 in pediatric T-cell acute lymphoblastic leukemia (TALL) patients and murine models 1. We next established that RasGRP1 overexpression results in a constitutively high GTP-loading rate of Ras, which is constantly counterbalanced by hydrolysis of RasGTP 2. In KRASG12D T-ALLs Ras does not rapidly cycle, instead it is trapped in the GTP-bound state. Thus, there are at least two biochemically distinct leukemogenic Ras signals 3. There are no effective K-, N-Ras, or RasGRP1- inhibitors to date and blocking oncogenic Ras signaling in the clinic remains a highly desired goal.
The Ras-PI3K signaling pathway is tumor-promoting in many types of cancer and has also been genetically linked to ~50% of T-ALL patients. Patterns of PI3K activation are not uniform in TALL cell lines and limited patient analyses. We utilized T-ALL as platform in combination with PI3K and mTOR inhibitors and high-throughput phospho-flow to systematically map PI3K signals in KRASG12D and RasGRP1-overexpressing T-ALLs, revealing heterogeneity and plasticity 4. Secondly, we utilized T-ALL as platform for fully saturated synthetic lethal screens with the pan-PI3K inhibitor GDC-0941 in combination with a high-complexity, barcoded shRNA library with up to 30 shRNA’s per single target 5. Results from these two directions that include analyses of combination therapy with 10 small molecule inhibitors, analysis of combination therapy in different cancer types, and in in vivo T-ALL preclinical mouse trials will be discussed.
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