Kian Lim, M.D., Ph.D.

Assistant Professor
Internal Medicine
Oncology

Immunology Program
Molecular Cell Biology Program

  • 314-362-6157

  • 314-362-7009

  • 8069

  • McDonnell Medical Sciences Bldg Rm 502

  • klim@dom.wustl.edu

  • https://sites.wustl.edu/limlab

  • NF-kB, Toll-like receptors, IRAK4, TAK1, KRAS, ERK, MK2

  • Understanding the role of inflammation in gastrointestinal cancers

Research Abstract:

The two ongoing research directions in my lab are:

1) Understanding the role of the innate immune inflammatory pathway in pancreatic and colon cancer.
Both intrinsic and extrinsic factors underlie the aggressive behavior and hence poor prognosis of PDAC. Intrinsically, PDAC cells are driven by strong oncogenic events including KRas mutants and hyperactivation of the NF-κB transcription factors. Extrinsically, the PDAC tumor microenvironment is highly fibrotic and rife with immune-suppressive myeloid cells. We recently found that PDAC cells "armored" themselves by activating the innate immune pathway, a self-defense mechanism that is normally summoned when cells are injured or invaded by microorganisms. PDAC cells frequently activate Interleukin-Receptor Associated Kinase 4 (IRAK4), the master switch that controls the innate immune signaling, to drive NF-κB activity and resist killing by chemotherapeutic agents. Supporting these findings, patients whose tumors show upregulated IRAK4 activity have a much poorer survival. Capitalizing on these observations, our lab is interested in (1) identifying how IRAK4 is activated in PDAC, relating specifically to the TLRs; (2) understanding the role of IRAK4, in immune and stromal fibroblasts in PDAC; and (3) devising novel therapeutic strategies that can be advanced into clinical trials. Our lab employs genetically-engineered mouse models (KPC and IRAK4 KO mice), patient-derived cancer cell lines and conventional PDAC cell lines to answer these questions. We are currently testing novel IRAK4 inhibitors in combination with chemotherapy and immunotherapy in genetic PDAC mouse models. In parallel, we are beginning to explore the importance of this pathway in colon cancer.

2) Targeting ERK1/2 in KRas-driven cancers. Activating mutations of KRas are the most common oncogenic event in human cancer. The KRas mutant protein exerts it oncogenic might by driving multiple signaling cascades. In collaboration with Dr. Andrea Wang-Gillam, we are testing a novel potent ERK1/2 inhibitor (BVD-523) in pancreatic cancer cell lines and mouse models. To this end, we have identified a few novel resistance mechanisms that could be simultaneously targeted to render ERK inhibition more effective in curbing KRas-driven cancer cell growth.

Selected Publications:

1. Zhang D, Li L, Jiang H, Li Q, Wang-Gillam A, Yu J, Head R, Liu J, Ruzinova MB, Lim KH. Tumor-Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer. Cancer Res. 2018 Apr 1;78(7):1700-1712. PubMed PMID: 29363544; PubMed Central PMCID: PMC5890818.

2. Zhang D, Li L, Jiang H, Knolhoff BL, Lockhart AC, Wang-Gillam A, et al. Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2017;23: 1748-1759.PMC5378683

3. Ngo VN*, Young RM*, Schmitz R*, Jhavar S*, Xiao W*, Lim KH*, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470: 115-119.PMC5024568 (*co-first authors)

4. Kashatus DF, Lim KH, Brady DC, Pershing NL, Cox AD, Counter CM. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol. 2011;13: 1108-1115.PMC3167028

5. Lim KH*, Brady DC*, Kashatus DF, Ancrile BB, Der CJ, Cox AD, et al. Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Mol Cell Biol. 2010;30: 508-523.PMC2798468 (*co-first authors)

6. Lim KH*, Ancrile BB*, Kashatus DF*, Counter CM. Tumour maintenance is mediated by eNOS. Nature. 2008;452: 646-649.PMC2688829 (*co-first authors)

7. Lee YS, Lim KH, Guo X, Kawaguchi Y, Gao Y, Barrientos T, et al. The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis. Cancer Res. 2008;68: 7561-7569.PMC2978070

8. Lim KH, O`Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol. 2006;16: 2385-2394

9. Lim KH, Counter CM. Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell. 2005;8: 381-392

10. Lim KH, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD, et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell. 2005;7: 533-545

Last Updated: 6/7/2018 12:32:43 PM

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