Welcome! We study the TAM family of receptor tyrosine kinases, comprised of TYRO-3, AXL, and MERTK, in cancer and the effect of TAM inhibition by small molecules as a 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, glioblastoma, 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, in collaboration with scientists at the University of North Carolina, the Graham lab 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, including MRX-2843, a first-in-class MERTK/FLT3-selective small molecule inhibitor that will advance to phase I clinical trials in 2018. Studies to determine the optimal application of MERTK inhibitors in combination with other agents to maximize therapeutic effects are ongoing.
Determine mechanisms of resistance to targeted MERTK inhibition.
Identify roles and effects of MERTK inhibition in early thymic precursor acute lymphoblastic leukemia.
Elucidate molecular pathways that can be targeted in combination with MERTK inhibition in acute myeloid leukemia.
Determine roles for TYRO-3, a protein related to MERTK, in acute myeloid leukemia.
Develop biomarkers of MERTK inhibition and therapeutic response in acute leukemia cells.
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 syngenic mouse models of leukemia and breast cancer.
Identification of immune biomarkers of MERTK inhibition and therapeutic effects.
Development of small molecule MERTK inhibitors for treatment of cancer
Stephen V. Frye, H. Shelton Earp III, Xiaodong Wang, Dmitri Kireev, University of North Carolina
Mediators of resistance to MERTK inhibition in acute myeloid leukemia
Jeff Tyner, Oregon Health Sciences University
Targeting MERTK for anti-thrombotic applications
Jorge DiPaola, Brian Branchford, University of Colorado
MERTK as a mediator of resistance to AXL-targeted therapies
Deric Wheeler, University of Wisconsin
Interactions between MERTK and STAT5 in leukemia stem cells
Kevin Bunting, Zhengqi Wang, Emory University
Roles for MERTK in glioblastoma
Dolores Hambardzumyan, Emory University
Nanoscale combination therapies for treatment of acute lymphoblastic leukemia
Erik Dreaden, Emory University
TAM kinases as mechanisms of resistance to chemotherapy in acute myeloid leukemia
Andy Kolb, Erin Crowgey, Nemours Hospital for Children & University of Delaware
Dawn Barnes, PhD
Graduate Studies: Emory University, 2016
Current Project: Elucidating the molecular pathways that synergize with MERTK inhibition in acute myeloid leukemia.
Fun Fact: I enjoy pyrography because it allows me to customize gifts for friends and family.
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.
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.
Justus Huelse, MS
Undergraduate: University of Konstanz, Germany
Graduate Studies: University of Copenhagen, Denmark
Fun Fact: I like to make my own cheeses.
Sherri Smart, MD, PhD
Katherine Minson, MD
Undergraduate: University of Pennsylvania
Graduate Studies: Medical University of South Carolina
Residency: Vanderbilt University, Nashville TN
Fellowship: University of Colorado at Denver and Emory University
Current Project: Understand mechanisms of bone marrow resistance to MERTK inhibition and nuclear MERTK
Ryan Summers, MD
Undergraduate: University of Georgia, Athens GA
Graduate Studies: Emory University School of Medicine, Atlanta GA
Residency: Emory University
Fellowship: Emory University
Fun Fact: I played quarterback for a team that won the high school football state championship in Texas.
Dan Yan, MD PhD
Graduate: Tongji Medical School, China
Fun Fact: Shopping, cooking, planting and traveling with my family to places that I've never been are things I enjoy.
Rebecca Parker, BS
Undergraduate: Tulane University, New Orleans, LA
Current Project: Mouse colony management and MERTK inhibition in NSCLC.
Fun Fact: I commute every day on my glitter-purple bike.
Sandra Christoph, MD, PhD (2011-2013), postdoctoral fellow
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
Leukemia and Lymphoma Society – Development of a novel FLT3 tyrosine kinase inhibitor with activity against D835Y and F691L mutant proteins
Swim Across America Research Grant – Development of a Novel Therapy Targeting MERTK and STAT5 in AML Stem Cells
CURE Childhood Cancer – MERTK Inhibitor Combination Therapy for Treatment of AML
American Cancer Society – Development of biomarkers of sensitivity to MRX2843, a dual MERTK and FLT3 inhibitor for treatment of acute myeloid leukemia in children
Precious Jules Foundation – Therapeutic targeting of MERTK and BCL-2 in Early T-Precursor acute lymphoblastic leukemia
Lee-Sherick AB, Jacobsen KM, Henry CJ, Huey MG, Parker RE, Page LS, Hill AA, Wang X, Frye SV, Earp HS, Jordan CT, DeRyckere D, Graham DK. MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity. JCI Insight. 2018 Nov 2;3(21).
McDaniel NK, Cummings CT, Iida M, Hülse J, Pearson HE, Vasileiadi E, Parker RE, Orbuch RA, Ondracek OJ, Welke NB, Kang GH, Davies KD, Wang X, Frye SV, Earp HS, Harari PM, Kimple RJ, DeRyckere D, Graham DK, Wheeler DL. MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents. Mol Cancer Ther. 2018 Nov;17(11):2297-2308.
Zhao J, Zhang D, Zhang W, Stashko MA, DeRyckere D, Vasileiadi E, Parker RE, Hunter D, Liu Q, Zhang Y, Norris-Drouin J, Li B, Drewry DH, Kireev D, Graham DK, Earp HS, Frye SV, Wang X. Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group. J Med Chem. 2018 Nov 21;61(22):10242-10254.
Yan D, Parker RE, Wang X, Frye SV, Earp HS, DeRyckere D, Graham DK. MERTK promotes resistance to irreversible EGFR tyrosine kinase inhibitors in non-small cell lung cancers expressing wild-type EGFR-family members. Clin Cancer Res. 2018 Sep 7.
Summers R, Minson KA, DeRyckere D, Graham DK. Roles for AXL and MERTK in Resistance to Cytotoxic and Targeted Therapies. ScienceDirect. 2018 April 20;3:61-85.
Huey MG, Minson KA, Earp HS, DeRyckere D, Graham DK. Targeting the TAM Receptors in Leukemia. Cancers (Basel). 2016 Nov 8;8(11). Review.
Sufit A, Lee-Sherick AB, DeRyckere D, Rupji M, Dwivedi B, Varella-Garcia M, Pierce AM, Kowalski J, Wang X, Frye SV, Earp HS, Keating AK, Graham DK. MERTK Inhibition Induces Polyploidy and Promotes Cell Death and Cellular Senescence in Glioblastoma Multiforme. PLoS One. 2016 Oct 26;11(10).
DeRyckere D, Lee-Sherick AB, Huey MG, Hill AA, Tyner JW, Jacobsen KM, Page LS, Kirkpatrick GG, Eryildiz F, Montgomery SA, Zhang W, Wang X, Frye SV, Earp HS, Graham DK. UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and In Combination with Methotrexate in Leukemia Models. Clin Cancer Research. 2016 Sep 20.
Lee-Sherick AB, Eisenman KM, Sather S, McGranahan A, Armistead PM, McGary CS, Hunsucker SA, Schlegel J, Martinson H, Cannon C, Keating AK, Earp HS, Liang X, DeRyckere D, Graham DK. Aberrant Mer Recepter Tyrosine Kinase Expression Contributes to Leukemogenesis in Acute Myeloid Leukemia. Oncogene. 2016 Dec 1;35(48):6270.
Minson KA, Smith CC, DeRyckere D, Libbrecht C, Lee-Sherick AB, Huey MG, Lasater EA, Kirkpatrick GD, Stashko MA, Zhang W, Jordan CT, Kireev D, Wang X, Frye SV, Earp HS, Shah NP, Graham DK. The MERTK/FLT3 Inhibitor MRX-2843 Overcomes Resistance-Conferring FLT3 Mutations in Acute Myeloid Leukemia. JCI Insight. 2016 Mar;1(3).
Cummings CT, Zhang W, Davies KD, Kirkpatrick GD, Zhang D, DeRyckere D, Wang X, Frye SV, Earp HS, Graham DK. Small Molecule Inhibition of MERTK is Efficacious in Non-Small Cell Lung Cancer Models Independent of Driver Oncogene Status. Mol Cancer Ther. 2015 Sep;14(9):2014-22.
Lee-Sherick AB, Zhang W, Menachof KK, Hill AA, Rinella S, Kirkpatrick G, Page LS, Stashko MA, Jordan CT, Wei Q, Liu J, Zhang D, DeRyckere D, Wang X, Frye S, Earp HS, Graham DK. Efficacy of a Mer and Flt3 Tyrosine Kinase Small Molecule Inhibitor, UNC1666, in Acute Myeloid Leukemia. Oncotarget. 2015 Mar 30;6(9):6722-36.
Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM Family: Phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014 Dec;14(12):769-85.
Cummings CT, Linger RM, Cohen RA, Sather S, Kirkpatrick GD, Davies KD, DeRyckere D, Earp HS, Graham DK. Mer590, A Novel Monoclonal Antibody Targeting MER Receptor Tyrosine Kinase, Decreases Colony Formation and Increases Chemosensitivity in Non-Small Cell Lung Cancer. Oncotarget. 2014 Nov 15;5(21)10434-45.
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||
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
International Journal of Molecular Medicine
Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies
Journal of Clinical Investigation
A Functional Landscape of Resistance to ALK
|Frederick H. Wilson||2015||Cancer Cell|
JAK/STAT pathway inhibition overcomes IL7-induced
A genomic screen identifies TYRO3
FLT3-driven redox-modulation of Ezrin regulates
|Aoife Corcoran||2013||Free Radical Research|
Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates
|Peter P Ruvulo||2015||Biochemica et Physica Acta|
UNC569-induced Morphological Changes in
|Ayako Sayama||2005||Toxicologic Pathology|
Near infrared imaging of Mer tyrosine kinase
|Miles A. Miller||2018||Chem. Commun.|
Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR
|Helena A Yu||2018||Clinical Cancer Research|
Ex vivo drug response profiling detects recurrent sensitivity patterns in
Intrinsic resistance to PIM kinase inhibition in AML through
An SH2 Domain-dependent, Phosphotyrosine-independent
|Nupam P Mahajan||2003||Journal of Biological Chemistry|
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
Effects of MERTK Inhibitors UNC569 and UNC1062
|Yuki Koda||2018||Anticancer Research|
A MicroRNA-7/Growth Arrest
|Tasnuva D Kabir||2018||Hepatology|
Diversification of TAM receptor tyrosine kinase function
|Anna Zagórska||2014||Nature Immunology|