MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system
The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia
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
Stephen V. Frye, H. Shelton Earp III, Xiaodong Wang 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
Yana Pikman, LEAP Consortium, Harvard University
Nanoscale combination therapies for treatment of acute leukemia
Erik Dreaden, Emory University
TAM kinases as mechanisms of resistance to chemotherapy in acute myeloid leukemia
Erin Crowgey and Andy Kolb, Nemours Hospital for Children & University of Delaware
Oncogenic roles for TAM kinases in the innate immune system
Curtis Henry, Emory University
Therapeutic modeling using patient-derived 3D bone marrow biomimicry cultures
Nicki Panoskaltsis, Winship Cancer Institute, Emory University
Sakis Mantalaris, Georgia Institute of Technology
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.
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.
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
Undergraduate: University of Central Arkansas
Graduate Studies: University of Arkansas for Medical Sciences
Residency: University of Cincinnati, Pediatric Hematology and Cincinnati Children's Hospital
Current Project: TYRO3 as a novel target for AML and the TAM family as targets in pediatric solid tumors.
Fun Fact: I can paint so realistic it looks like a photograph!
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.
Brittany Smith, BS
Undergraduate: Emory University
Current project: MERTK/TYRO3 inhibition in NSCLC
Fun Fact: Before college, I lived in 8 different places!
Travon Baxter, MS
Undergraduate: Tuskegee University
Graduate: University of Maryland College Park
Current Project: Intra-thoracic transplantation of mouse lung cancer and human NSCLC.
Fun Fact: I have a red-eared slider turtle that completely ignores me named "LOU"!
K.M. Tanim, MS
Undergraduate School: Khulna University, Bangladesh
Graduate School: West Virginia State University
Current Project: The role of intracellular MERTK signaling in cancer progression.
Fun Fact: I once jumped out of a plane.
Diana Fridlyand , MD
Undergraduate: Emory University
Graduate Studies: Medical College of Georgia/ Augusta University
Residency: Medical College of Georgia/ Augusta University
Fun Fact: I speak Russian!
Madison Stout, BS
Undergraduate: University of Alabama
Current project: Mertk and Chemotherapy Combination Therapies in T-ALL
Fun Fact: I have two cats!
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
Swim Across America Research Grant – Combined MERTK and STAT5 inhibition to target AML stem cells
CURE Childhood Cancer – TAM kinases as mediators of chemoresistance in AML
American Cancer Society – Biomarkers of sensitivity to MRX2843 in AML
No More Kids with Cancer – Targeting MERTK in combination with chemotherapy or immune checkpoint inhibitors in T-cell ALL
NCI Lung SPORE – Targeting MERTK to improve outcomes for EGFR-mutated NSCLC
NCI R01 – Development of dual MERTK and AXL inhibitors
Huelse, Justus M et al. MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system. Pharmacology & therapeutics vol. 213 (2020): 107577. doi:10.1016/j.pharmthera.2020.107577
Smart SK, Vasileiadi E, Wang X, DeRyckere D, Graham DK. The Emerging Role of TYRO3 as a Therapeutic Target in Cancer. Cancers (Basel). 2018;10(12):474. Published 2018 Nov 29. doi:10.3390/cancers10120474
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.
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.
PNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway
|2020||Cell Death & Differentiation|
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|
MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia
María Luz Morales
A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity
|Jonathan Rios-Doria||2020||Frontiers in Oncology|
Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma
|Vikas A Gupta||2017||Blood|
STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells
|Daniel Ribeiro||2018||Blood Advances|
Immune Cell Composition in Human Non-small Cell Lung Cancer
|Branislava Stankovic||2019||Frontiers in Immunology|
Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection
|Tom Adomati||2020||Cell Reports|
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
|George M Burslem||2018||Cell Chem Biology|
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
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)||
|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|
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|