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

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. 

Email: deborah.deryckere@emory.edu


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. 

Email: debarne@emory.edu

 


Justus Huelse, MS

Undergraduate: University of Konstanz, Germany

Graduate Studies: University of Copenhagen, Denmark

Fun Fact: I like to make my own cheeses.

Email: justus.hulse@emory.edu


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!

Email: Sherri.Smart@choa.org


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.

Email: Ryanjsumme@emory.edu


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.

Email: danyan2@emory.edu


Brittany Smith, BS

Undergraduate: Emory University

Current project: MERTK/TYRO3 inhibition in NSCLC

Fun Fact: Before college, I lived in 8 different places!

Email: Brittany.Smith2@emory.edu


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"!

Email: Tbaxte3@emory.edu


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.

Email: ktanim@emory.edu 


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!

Email: dfridly@emory.edu

Katherin 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

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.

 

View more publications

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
Inhibition in Lung Cancer

Frederick H. Wilson 2015 Cancer Cell
1/17/18

JAK/STAT pathway inhibition overcomes IL7-induced
glucocorticoid resistance in a subset of human T-cell acute
lymphoblastic leukemias

C Delado-Martin 2017 Leukemia
1/31/18

A genomic screen identifies TYRO3
as a MITF regulator in melanoma

Shoutian Zhu 2009 PNAS
2/17/18

FLT3-driven redox-modulation of Ezrin regulates
leukaemic cell migration

Aoife Corcoran 2013 Free Radical Research
2/21/18

Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates
both p53 wild type and p53 null AML cells

Peter P Ruvulo 2015 Biochemica et Physica Acta
3/7/18

UNC569-induced Morphological Changes in
Pigment Epithelia and Photoreceptor Cells in
the Retina through MerTK Inhibition in Mice

Ayako Sayama 2005 Toxicologic Pathology
3/14/18

Near infrared imaging of Mer tyrosine kinase
(MERTK) using MERi-SiR reveals tumor associated
macrophage uptake in metastatic disease

Miles A. Miller 2018 Chem. Commun.
3/21/18

Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR
kinase inhibitors and characterization of MTOR as a mediator of resistance.

Helena A Yu 2018 Clinical Cancer Research
4/4/18

Ex vivo drug response profiling detects recurrent sensitivity patterns in
drug-resistant acute lymphoblastic leukemia

Viktoras Frismantas 2017 Blood
4/18/18

Intrinsic resistance to PIM kinase inhibition in AML through
p38α-mediated feedback activation of mTOR signaling

Diede Brunen 2016 Oncotarget
5/9/18

An SH2 Domain-dependent, Phosphotyrosine-independent
Interaction between Vav1 and the Mer Receptor Tyrosine Kinase

Nupam P Mahajan 2003 Journal of Biological Chemistry
5/16/18

PDG FRβ translocates to the nucleus and regulates
chromatin remodeling via TATA element–modifying
factor 1

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
on the Growth of Acute Myeloid Leukaemia Cells

Yuki Koda 2018 Anticancer Research
6/13/18

A MicroRNA-7/Growth Arrest
Specific 6/TYRO3 Axis Regulates
the Growth and Invasiveness
of Sorafenib-Resistant Cells in Human
Hepatocellular Carcinoma

Tasnuva D Kabir 2018 Hepatology
6/20/18

Diversification of TAM receptor tyrosine kinase function

Anna Zagórska 2014 Nature Immunology