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

Associate Professor
Internal Medicine
Oncology

Cancer Biology Program
Immunology Program
Molecular Cell Biology Program

  • 314-362-6157

  • 314-362-7009

  • 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 major research directions in my lab are:

1) Understanding the role of the innate immune inflammatory pathway in pancreatic and colon cancers. The tumor microenvironment of pancreatic cancer 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.

Mentorship and Commitment to Diversity Statement:
As a 1st generation Asian American I have the first hand experience on racial, and all kinds of inequalities, which I strongly believe are obstacles to progress and deeply harmful to our society.

As a proud leader of the GI oncology team and my own lab, I firmly uphold the beliefs in gender, racial, religious, sexual orientation, national, socioeconomic equalities. My lab consists of members from six different countries and different races. Our clinical GI Oncology team consists of members from various countries and ethnicities. We all share a common goal of improving the care and outcome of patients with gastrointestinal cancers.

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

4. Dodhiawala PB, Khurana N, Zhang D, Cheng Y, Li L, Wei Q, Seehra K, Jiang H, Grierson PM, Wang-Gillam A, Lim KH. TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations. J Clin Invest. 2020 Jun 23:137660. doi: 10.1172/JCI137660.

5. Li Q, Chen Y, Zhang D, Grossman J, Li L, Khurana N, Jiang H, Grierson PM, Herndon J, DeNardo DG, Challen GA, Liu J, Ruzinova MB, Fields RC, Lim KH. IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer. JCI Insight. 2019 Oct 3;4(19). pii: 130867. doi: 10.1172/jci.insight.130867. PMID: 31527315

6. Jiang H, Xu M, Li L, Grierson P, Dodhiawala P, Highkin M, Zhang D, Li Q, Wang-Gillam A, Lim KH. Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models. Molecular cancer therapeutics. 2018;17(10):2144-55.

7. 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)

8. 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

9. 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)

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

11. 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

12. 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

13. 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

14. 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: 3/23/2021 1:47:08 PM

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