Overview
Welcome! We study members of the TAM-family of receptor tyrosine kinases (TYRO3, AXL, and MERTK) in cancer and the effects of TAM inhibition asa disease treatment.
The receptor tyrosine kinase MERTK was first discovered by Dr. Graham and subsequent work in the Graham lab demonstrated oncogenic roles for MERTK in a variety of solid tumor and hematologic malignancies. Current projects focused on acute leukemia, non-small cell lung cancer and melanoma are aimed at better understanding the biology of MERTK and related receptors in tumor cells and their roles in the human immune system. In addition, we developed and characterized a series of novel small molecules that selectively and potently inhibit MERTK with the goal of targeting MERTK to treat patients with cancer. The lead compound, MRX-2843, is a first-in-class dual MERTK and FLT3-selective tyrosine kinase inhibitor that is currently being tested in phase I clinical trials. Studies to determine the optimal application of MERTK inhibitors in combination with other agents to maximize therapeutic effects are ongoing. We are also working with collaborators to develop additional classes of novel inhibitors targeting the TAM kinases.
Determine mechanisms of resistance to MERTKinhibition.
Identify roles and effects of MERTK inhibition in early thymic precursor acute lymphoblastic leukemia (ETP-ALL).
Elucidate molecular pathways that can be targeted in combination with MERTK inhibition to enhance therapeutic efficacy against acute myeloid leukemia (AML).
Determine oncogenic roles for TYRO3 in AML.
Develop biomarkers of MERTK inhibition and therapeutic response.
Identify tyrosine kinase inhibitors that synergize with MERTK inhibition to suppress tumor growth.
Determine roles for MERTK in resistance to third-generation EGFR tyrosine kinase inhibitors in non-small cell lung cancers with activating EGFR mutations.
Determine immunomodulatory roles for MERTK in the tumor microenvironment using syngeneic mouse models of leukemia and lung cancer.
Identify immune biomarkers of MERTK inhibition and therapeutic effects.
Development of small molecule TAM kinase inhibitors for treatment of cancer
Xiaodong Wang, Stephen V. Frye, H. Shelton Earp III, and Dmitri Kireev, University of North Carolina – Chapel Hill
Mediators of resistance to MERTK inhibition in acute myeloid leukemia
Jeff Tyner, BEAT AML Project, Oregon Health Sciences University
Therapeutic modeling using patient-derived 3D bone marrow biomimicry cultures
Nicki Panoskaltsis, Trinity College Dublin
Sakis Mantalaris, Trinity College Dublin
Targeting MERTK in the tumor immune microenvironment
Susan Thomas, Georgia Institute of Technology
Curtis Henry, University of Colorado
Douglas K. Graham, MD, PhD
Undergraduate: Wake Forest University
Graduate Studies: University of North Carolina (MD, PhD)
Post-doctoral: University of Colorado/Children's Hospital Colorado
Fun Fact: I once rappelled down the tallest building in Denver to raise money for cancer research.
Deb DeRyckere, PhD
Undergraduate: University of Michigan
Graduate Studies: University of California- Berkeley
Post-doctoral: University of Colorado School of Medicine
Fun Fact: Once stared a polar bear in the eye from one foot away.
Email: deborah.deryckere@emory.edu
Justus Huelse, PhD
Postdoctoral Research Fellow
PhD, Emory University, 2023
justus.hulse@emory.edu
G. Humber
Research Specialist
BS, University of Alabama, 2022
ghumber@emory.edu
Edward Henderson
Emory Graduate Student, Cancer Biology
BS, Davidson College, 2018
edward.benton.henderson@emory.edu
Alejandro de Janon
Georgia Tech/Emory Graduate Student, Bioengineering
MS, Texas A&M University, 2020
BS, Universidad Tecnológica Nacional 2015
adejan4@emory.edu
Aashis Thapa
Emory Graduate Student, Cancer Biology
BA, Reed College, 2015
aashis.thapa@emory.edu
Dan Yan, MD, PhD
Assistant Professor of Pediatrics
MD, Tongji Medical School, China
danyan2@emory.edu
Tsz Yau (Jessica) Yeung
Lead Research Specialist
BS, Emory University, 2020
jessica.yeung@emory.edu
Juhye Yim
Emory Graduate Student, Cancer Biology
MS, Yonsei University 2020
BS, SUNY Fredonia, 2018
jyim28@emory.edu
Dawn Barnes
Sherri Smart
Ryan Summers
Brittany Smith
Travon Baxter
Diana Fridyland
Madison Chimenti
Katherine Minson, MD (2013-2019), pediatric hematology/oncology fellow, Assistant Professor
Eleana Vasileiadi, MD (2017-2019), visiting scholar, University of Athens School of Medicine, Greece
Kristen Jacobsen, PhD (2009-2018), graduate student, immunology program; postdoctoral fellow
Sheng Zheng, PhD (2014-2016), visiting scholar, Northeast Dianli University, China
Alexandra Sufit (2014-2015), graduate student, Cancer Biology
Lenka Teodorovic, PhD (2013-2015), postdoctoral fellow
Christopher Cummings (2011-2015), graduate student, Medical Scientist Training Program (MSTP)
Alisa Lee Sherick, MD (2010-2015), pediatric hematology/oncology fellow
Sandra Christoph, MD, PhD (2011-2013), postdoctoral fellow
Amy Keating, MD (2003-2013), pediatric hematology/oncology fellow
Jennifer Schlegel (2010-2012), graduate student, Program in Molecular Biology
Justine Migdall (2009-2012), graduate student, Medical Scientist Training Program (MSTP)
Rachel Linger, PhD (2007-2012), postdoctoral fellow
Luis Pessoa-Brandao, PhD (2007-2012), postdoctoral fellow
Kristen Eisenman, MD (2008-2011), pediatric hematology/oncology fellow
Kelly Sawczyn, MD (2004-2007), pediatric hematology/oncology fellow
Dana Salzberg, MD (2002-2006), pediatric hematology/oncology fellow
NCI R01 – Novel TYRO3 inhibitors for treatment of cancer
Eschelman Institute for Innovation – Novel TYRO3 degraders for treatment of cancer
Donaldson Charitable Trust – Targeting MERTK to improve immunotherapeutic response in NSCLC
NCI Lung SPORE – Targeting MERTK to improve outcomes for EGFR-mutated NSCLC
NCI R01 – Development of dual MERTK and AXL inhibitors
DeRyckere, D., Huelse, J. M., Earp, H. S., & Graham, D. K. (2023). TAM family kinases as therapeutic targets at the interface of cancer and immunity. Nature Reviews Clinical Oncology, 20(11), 755-779.
Kelvin, J. M., Chimenti, M. L., Zhang, D. Y., Williams, E. K., Moore, S. G., Humber, G. M., Baxter, T. A., Birnbaum, L. A., Qui, M., Zecca, H., Thapa, A., Jain, J., Jui, N. T., Wang, X., Fu, H., Du, Y., Kemp, M. L., Lam, W. A., Graham, D. K., DeRyckere, D., … Dreaden, E. C. (2023). Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia. Journal of controlled release : official journal of the Controlled Release Society, 361, 470–482.
Yan, D., Huelse, J. M., Kireev, D., Tan, Z., Chen, L., Goyal, S., ... & Graham, D. K. (2022). MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer. The Journal of Clinical Investigation, 132(15).
Summers, R. J., Jain, J., Vasileiadi, E., Smith, B., Chimenti, M. L., Yeung, T. Y., ... & Graham, D. K. (2022). Therapeutic targeting of MERTK and BCL-2 in T-cell and early T-precursor acute lymphoblastic leukemia. Cancers, 14(24), 6142.
Sinik, L., Minson, K. A., Tentler, J. J., Carrico, J., Bagby, S. M., Robinson, W. A., ... & Graham, D. K. (2019). Inhibition of MERTK promotes suppression of tumor growth in BRAF mutant and BRAF wild-type melanoma. Molecular cancer therapeutics, 18(2), 278-288.
Lee-Sherick, A. B., Jacobsen, K. M., Henry, C. J., Huey, M. G., Parker, R. E., Page, L. S., ... & Graham, D. K. (2018). MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity. JCI insight, 3(21).
Minson, K. A., Smith, C. C., DeRyckere, D., Libbrecht, C., Lee-Sherick, A. B., Huey, M. G., ... & Graham, D. K. (2016). The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI insight, 1(3).
DeRyckere, D., Lee-Sherick, A. B., Huey, M. G., Hill, A. A., Tyner, J. W., Jacobsen, K. M., ... & Graham, D. K. (2017). UNC2025, a MERTK small-molecule inhibitor, is therapeutically effective alone and in combination with methotrexate in leukemia models. Clinical Cancer Research, 23(6), 1481-1492.
Date | Title | First Author | Year | Journal |
---|---|---|---|---|
4/7/21 |
PNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway |
Wenwen Du |
2020 | Cell Death & Differentiation |
3/10/21 |
Expression of TAM-R in Human Immune Cells and Unique Regulatory Function of MerTK in IL-10 Production by Tolerogenic DC |
Paul Giroud | 2020 | Frontiers in Immunology |
3/3/21 |
MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia |
María Luz Morales |
2019 | Nature Research |
2/24/21 |
A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity |
Jonathan Rios-Doria | 2020 | Frontiers in Oncology |
2/3/21 |
Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma |
Vikas A Gupta | 2017 | Blood |
1/13/21 |
STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells |
Daniel Ribeiro | 2018 | Blood Advances |
12/9/20 |
Immune Cell Composition in Human Non-small Cell Lung Cancer |
Branislava Stankovic | 2019 | Frontiers in Immunology |
12/1/20 |
Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection |
Tom Adomati | 2020 | Cell Reports |
12/1/20 |
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study |
George M Burslem | 2018 | Cell Chem Biology |
Date | Title | First Author | Year |
Journal |
1/2/19 |
EGFR in Tumor-Associated Myeloid Cells Promotes Development of Colorectal Cancer in Mice and Associates With Outcomes of Patients. |
Sriram Srivatsa and Mariel C. Paul | 2017 |
Gastroenterology |
1/9/19 |
MicroRNA-7 inhibits colorectal cancer cell proliferation, migration and invasion via TYRO3 and phosphoinositide 3-kinase/protein B kinase/mammalian target of rapamycin pathway suppression |
Anchen Qin | 2018 |
International Journal of Molecular Medicine |
1/16/19 |
Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies |
Kariolis Mihalis |
2017 |
Journal of Clinical Investigation |
1/30/19 |
MERTK as negative regulator of human T cell activation |
Raquel Cabezón | 2015 | Journal of Leukocute Biology |
2/6/19 | ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia | Mark A. Gregory | 2016 | PNAS |
3/6/19 | Negative regulation of G1/S transition by the candidate bladder tumour suppressor gene DBCCR1 | Hiroyuki Nishiyama | 2001 | Oncogene |
3/13/19 | TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer | Florent Dufour | 2019 | British Journal of Cancer |
3/20/19 | Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation | Changshan Wang | 2018 | Journal of Clinical Investigation |
3/27/19 | Pan-TAM tyrosine kinase inhibitor BMS-777607 enhances anti-PD-1 mAb efficacy in a murine model of triple-negative breast cancer | Canan Kasikara | 2019 | Cancer Research |
5/1/19 | MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression | Yao Jiang | 2019 | Nature Communications |
5/8/19 | PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia | Ingrid M. Ariës | 2018 | Journal of Experimental Medicine |
8/7/19 | A novel human anti‐AXL monoclonal antibody attenuates tumour cell migration ( Brittany Smith - Presenter) | Yanting Duan | 2018 | Experimental Immunology |
8/21/19 | TAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL ( Tanim Ahasan - Presenter) |
Ayaz Najafov |
Molecular Cell | |
8/28/19 | Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations ( Ryan Summers- Presenter) | Emilee Senkevitch | 2018 | Oncotarget |
Date | Title | First Author | Year | Journal |
---|---|---|---|---|
1/10/18 |
A Functional Landscape of Resistance to ALK |
Frederick H. Wilson | 2015 | Cancer Cell |
1/17/18 |
JAK/STAT pathway inhibition overcomes IL7-induced |
C Delado-Martin | 2017 | Leukemia |
1/31/18 |
A genomic screen identifies TYRO3 |
Shoutian Zhu | 2009 | PNAS |
2/17/18 |
FLT3-driven redox-modulation of Ezrin regulates |
Aoife Corcoran | 2013 | Free Radical Research |
2/21/18 |
Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates |
Peter P Ruvulo | 2015 | Biochemica et Physica Acta |
3/7/18 |
UNC569-induced Morphological Changes in |
Ayako Sayama | 2005 | Toxicologic Pathology |
3/14/18 |
Near infrared imaging of Mer tyrosine kinase |
Miles A. Miller | 2018 | Chem. Commun. |
3/21/18 |
Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR |
Helena A Yu | 2018 | Clinical Cancer Research |
4/4/18 |
Ex vivo drug response profiling detects recurrent sensitivity patterns in |
Viktoras Frismantas | 2017 | Blood |
4/18/18 |
Intrinsic resistance to PIM kinase inhibition in AML through |
Diede Brunen | 2016 | Oncotarget |
5/9/18 |
An SH2 Domain-dependent, Phosphotyrosine-independent |
Nupam P Mahajan | 2003 | Journal of Biological Chemistry |
5/16/18 |
PDG FRβ translocates to the nucleus and regulates |
Natalia Papadopoulos | 2018 | Journal of Cell Biology |
5/30/18 | Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme |
Y Wang | 2012 | Oncogene |
6/6/18 |
Effects of MERTK Inhibitors UNC569 and UNC1062 |
Yuki Koda | 2018 | Anticancer Research |
6/13/18 |
A MicroRNA-7/Growth Arrest |
Tasnuva D Kabir | 2018 | Hepatology |
6/20/18 |
Diversification of TAM receptor tyrosine kinase function |
Anna Zagórska | 2014 | Nature Immunology |