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BCN057, a Modulator of GSK3β, Induces KRAS G12D Mutant Pancreatic Cancer Cell Death

Elizabeth M. Singer, Rishi Man Chugh, Payel Bhanja, Adrian Gomez, Lucy Gao, Julian P. Whitelegge, William H. McBride, Subhrajit Saha, Andrew J. Norris
doi: https://doi.org/10.1101/2021.09.03.458938
Elizabeth M. Singer
1BCN Bio Sciences, Pasadena, CA, USA
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Rishi Man Chugh
2Department of Radiation Oncology, The University of Kansas Medical Center, MS 4033, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA
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Payel Bhanja
2Department of Radiation Oncology, The University of Kansas Medical Center, MS 4033, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA
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Adrian Gomez
3Department of Chemistry and Biochemistry, University of California Los Angeles CA, USA
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Lucy Gao
4The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute of Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles CA
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Julian P. Whitelegge
4The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute of Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles CA
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William H. McBride
5Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles CA
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Subhrajit Saha
2Department of Radiation Oncology, The University of Kansas Medical Center, MS 4033, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA
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Andrew J. Norris
1BCN Bio Sciences, Pasadena, CA, USA
4The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute of Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles CA
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  • For correspondence: andrew@bcnbio.com
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Abstract

Effective treatment for Pancreatic Cancer remains a major challenge due to its resistance to radiation/chemotherapy and poor drug permeability. Moreover, treatment induced normal tissue toxicity, mainly to the duodenum and gastrointestinal epithelium, is common and is a dose limiting event, while toxicity to the pancreas is relatively rare1–3. Gastrointestinal toxicity, however, often results in interruption, reduction or premature withdrawal of anti-cancer therapy which is a very significant factor impacting the overall survival of patients being treated. Therefore, development of a therapeutic strategy to selectively sensitize tumor tissue without inducing normal tissue toxicity is important. In this manuscript, we show that the novel small molecule BCN057 can modulate chemo-sensitivity of oncogenic RAS pancreatic cancer cells while conversely protecting normal intestinal epithelium from off target toxicity. In particular, BCN 057 protects Lgr5 positive intestinal stem cells, thereby preserving barrier function. Further, it is demonstrated that BCN057 inhibits GSK3β and thereby induces a pro-apoptotic phosphorylation pattern on c-Jun in KRAS G12D mutant pancreatic cancer cells (Panc-1) leading to the restoration of PTEN expression and consequent apoptosis. This appears to be a new mechanistic observation for the oncogenic RAS phenotype. Lastly, concurrent with its GSK3β inhibition, BCN057 is a small molecule inhibitor of PD-1 expression on human T-lymphocytes co-cultured with human pancreatic cancer cells. In summary, BCN057 can promote synthetic lethality specifically to malignant cells and therefore should be considered to improve the therapeutic ratio in pancreatic and epithelial cancer treatment in conjunction with chemotherapy and radiation.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 10, 2021.
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BCN057, a Modulator of GSK3β, Induces KRAS G12D Mutant Pancreatic Cancer Cell Death
Elizabeth M. Singer, Rishi Man Chugh, Payel Bhanja, Adrian Gomez, Lucy Gao, Julian P. Whitelegge, William H. McBride, Subhrajit Saha, Andrew J. Norris
bioRxiv 2021.09.03.458938; doi: https://doi.org/10.1101/2021.09.03.458938
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BCN057, a Modulator of GSK3β, Induces KRAS G12D Mutant Pancreatic Cancer Cell Death
Elizabeth M. Singer, Rishi Man Chugh, Payel Bhanja, Adrian Gomez, Lucy Gao, Julian P. Whitelegge, William H. McBride, Subhrajit Saha, Andrew J. Norris
bioRxiv 2021.09.03.458938; doi: https://doi.org/10.1101/2021.09.03.458938

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