Abstract B13: Novel treatment strategy for pancreatic cancer by targeting the ‘undruggable’ Ras oncoprotein
Bibliographic record
Abstract
Abstract Background and Aims: Mutations in RAS and various other components of the Ras signaling pathways are among the most common genetic alterations in human cancers, including up to 25% of lung cancers and over 90% of pancreatic cancers. Ras function as ‘molecular switches’ in a number of signaling pathways that regulate vital cellular functions. Over the past few decades, it has become clear that the activity or the oncogenic potential of Ras is dependent on the non-receptor tyrosine kinase Src to regulate essential cellular pathways for proliferation, differentiation and survival of eukaryotic cells. Recently, we showed that Src binds to and phosphorylates Ras on a conserved tyrosine residue at position 32 within the switch I region to promote Ras GTPase activity. We then identified Shp2 as the critical tyrosine phosphatase that is responsible for the dephosphorylation and activation of Ras. However, it is unknown whether pharmacologic manipulation of Shp2 activity would suppress the growth of Ras-driven pancreatic cancer (PDACs), a highly aggressive disease currently without effective treatment options or cure. Methods: We generated the available Ras, Src, and SHP2 reagents (wild-type, oncogenic, truncation, dominant-negative, catalytically active or inactive, mutants) to determine the structure/function relationship between Ras, Src, and SHP2. The interaction was assessed by immunoprecipitation and western blotting. We utilized several PDAC cell lines and patient-derived xenografts cell lines (PDX-C). The cell growth was evaluated by Alarmar Blue assay. Results: We identified SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signaling. In comparison to K-Ras WT pancreatic cancer cells, the level of phospho-Shp2 was observed to be higher in K-Ras mutated cell lines in both absence and presence of growth factors. Pharmacologic inhibition of Shp2 using a specific cell-permeable Shp2 inhibitor decreased the level of phosphorylation of Shp2 as well as downstream signaling such as pAKT and pERK especially in the presence of growth factor. Notably, we show that treatment with this inhibitor suppressed the cell proliferation in both K-Ras WT and mutated pancreatic cancer cells as well as PDX-C in a caspase-dependent manner. Conclusion: Our results identify SHP2 as a direct activator of Ras and potential therapeutic target for pancreatic cancer driven by a previously ‘undruggable’ oncogenic or hyperactive Ras. Citation Format: Yoshihito Kano, Severa Bunda, Jen Jen Yeh, Zhong-Yin Zhang, Michael Ohh.{Authors}. Novel treatment strategy for pancreatic cancer by targeting the ‘undruggable’ Ras oncoprotein. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B13.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".