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AXL: A key regulator of EMT and clinical implications
JOSEPHINE A. TAVERNA, MD
DRUG DEVELOPMENT FELLOW
CTRC‐UTHSCSA
Financial Disclosure
Josephine Taverna, MD, has no relevant financial relationships with commercial interests to disclose.
AXLAXL belongs to the TAM (Tyro3, AXL, Mer) RTK family
Key regulator of EMT
AXL activation : Growth arrest specific 6 (Gas6) ligand binds to its extracellular domain and activation of important downstream signaling pathways
EMT and Tumor Progression
Thiery JP Cell 2009;139:871‐90
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E-cadherin-mediated cell–cell adherens junctions and cell–ECM integrin-mediated
adhesions
Canel et al. J Cell Sci. 2013 Jan 15;126(Pt 2):393‐401.
High Axl expression results from pharmacologic selective pressure to chemotherapy and targeted agents and accessed the mechanism of acquired drug resistance‐Resistance phenotype frequently accompanied by EMT and can be reverted by AXL
AXL expression indirectly correlates with overall survival in cholangiocarcinoma
Li et al. Cancer Letters 2014.
Inhibiting RTK AXL reduces GBM growth, migration, and invasion
Onken et al. Oncotarget 2015.
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AXL expression and tumor expressionTumor type Tumor Biology References
Esophageal SCC Adverse prognosis and distant metastasis Hsieh et al. Oncotarget 2016.
Cholangiocarcinoma Significant correlation between high YAP1 and AXL expression levels and worse prognosis. Li et al. Cancer Letters 2014
Glioblastoma Inhibiting RTK AXL reduces glioblastoma growth, migration, and invasion Onken et al. Oncotarget 2015.
Hepatocellular carcinoma Axl pathway promotes tumor invasion through the transcriptional activation of Slug Lee et al. Carcinogenesis 2014
Head and Neck cancer Tumor‐Associated Macrophages Promotes tumor progression through AXL activation Lee et al. Ann Surg Oncol. 2014
B‐cell CLL The novel receptor tyrosine kinase Axl is constitutively active Ghosh et al. Blood 2011
AML Axl is important for constitutive FLT3 phosphorylation in FLT3‐ITD1 + AML Park et al. Myeloid Neoplasia 2016.
NSCLC Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis,blocks growth and enhances chemosensitivity
Linger et al. Oncogene 2013.
Melanoma shRNA‐mediated inhibition of MERTK resulted in increased cell death, decreased proliferation, decreased colony formation, decreased migration, and decreased tumor formation in xenografts
Schlegel et al. J Clin Invest 2013. Tworkoski et al. Pigment CellMelanoma Res 2013
Ovarian adenocarcinoma Novel Axl‐driven signaling pathway predicts poor clinical outcome. Genetic inhibition of AXL in human metastatic ovarian tumor cells prevent the initiation of metastatic disease in vivo.
Rea et al. Oncotarget 2015. Rankin et al. Cancer Research 2010.
Pancreatic Cancer AXL‐knockdown Panc‐1 cells decreased in vitro cell migration, survival, proliferation, growth Leconet et al. Oncogene 2014.
Prostate Cancer GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival Shiozawa et al. Neoplasia 2010.
Renal Cell Cancer Direct regulation of GAS6/AXL signaling by HIF promotes through SRC and MET Rankin et al. Proc Natl Acad Natl Sci2014.
AXL and Treatment Resistance Drug Resistance Mechanisms of Resistance References
HNSCC &Esophageal SCC
AXL Mediates Resistance to PI3Ka Inhibition byActivating the EGFR/PKC/mTOR Axis
Elkabets et al. Cancer Cell 2015
Ovarian cancer cells Targeting Axl and Tyro3 receptor tyrosine kinases can circumvent taxol resistance Suh et al. Internat J Oncol2015.
NCSLC Cisplatin was associated with epithelial–mesenchymal transition (EMT) mediated drug resistance and AXL tyrosine kinase‐mediated increased cell motility.
Kurokawa et al. Cancer Science 2013.
TNBC, NSCLC • AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs• Anti‐Axl mAb can enhance the therapeutic efficacy of anti‐VEGF,EGFR small‐molecule inhibitors and chemotherapy
Wilson et al. Cancer Research 2014.
TNBC, NSCLC Anti‐Axl mAb can enhance the therapeutic efficacy of anti‐VEGF,EGFR small‐molecule inhibitors as well as chemotherapy
Ye et al. Oncogene 2010.
Breast Cancer Gas6/Axl Axis Contributes to Chemoresistance and Metastasis through Akt/GSK‐3β/β‐catenin Signaling
Wang et al. Theranostics2016.
chronic myeloid leukaemia(CML) cells.
TAM receptor AXL and the cytoplasmic kinases LYN and SYK is involved in nilotinib‐resistance Gioia et al. J Pathology 2015.
Triple negative breast cancer (TNBC)‐accounts for 10% to 27% of breast cancer(BC)
‐characterized by an absence of HER‐2, ER/PR receptor
‐no targeted therapies exist!
‐TNBC displays an aggressive tumor biology driven by EMT and has a high propensity for the development of distant metastasis
AXL: an essential EMT‐induced regulator of breast cancer metastasis and patient survival60% primary BC do not express Axl
Axl is overexpressed in metastatic sites and is required for lymphatic and/or hematogenousspread in both BC patients and mice xenograft models
High Axl expression in primary BC tumors independently predicts poor OS in BC patients
AXL is detected at higher levels in metastases compared to normal tissues or primary tumors
Axl not down prevent spread of highly metastatic breast cancer cells from mammary glands to lymph nodes and several major organs thereby increasing overall survival
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Axial expression investigated in a panel of 190 breast cancers and sized matched group of tumors detected by mammography screening
Gjerdrum et al. PNAS 2010
Axl is up‐regulated by EMT inducers in breast epithelial cells.
Gjerdrum et al. PNAS 2010
Drug Sensitivity of Axl inhibitors in resistant TNBC cell linesMPCD84111 is a quinolinyloxyphenylsulfonamides TKI patented as an AXL inhibitor
study demonstrates the impact of TKI (MPCD84111) on Axl phosphorylation and the migration as well as viability of MDA‐MB‐231, BT549, Hs5785
Cellular target profiling assay:◦ MPCD84111 demonstrated 50% decrease in the activity of SFK (Src, Lyn, Fyn, Yes) and other kinases (Abl, PTK5, EGFR, ErbB4, Lok, Tie2)
◦ MPCD84111 generally affected the Met‐related kinases (Met, Ron) and the Aurora kinases (Aurora A/B/C)
Penzes et al. Cancer Biology & Therapy 2014
Axl is constitutively active in B‐cell chroniclymphocytic leukemia and acts as a docking site of nonreceptor kinases
P‐Axl was correlated with the other constitutively phosphorylated kinases ‐ Lyn, PI3K, SyK, phospholipase Cg2 in CLL B cells
Gosh et al. found that these intracellular signaling molecules were complexed with P‐Axl in primary CLL B cells
When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI‐606), or a specific‐inhibitor of Axl (R428), robust induction of CLL B‐cell apoptosis was observed in both a dose‐ and time‐dependent manner
Axl is a novel RTK identified in CLL B cells which appears to work as a docking site for multiple non‐RTKs and drives leukemic cell survival signals
Ghosh et al. Blood 2011
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AML: AXL overexpression confers drug resistance
Hong et al. Cancer Letters 268 (2008) 314–324
In vitro studies
AXL Mediates Resistance to PI3Ka Inhibition by Activating the EGFR/PKC/mTOR Axis
What is the role of AXL inhibitor therapy in treatment resistant TNBC cell lines?
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Sensitivity of TNBC cell lines to the anti‐proliferative and cytotoxic effects of MTAs
Risinger, Dybal‐Hargreaves and Mooberry et al. Anticancer Res 2015
TP‐0903 alone HCC1937 BT‐549 MDA‐MB‐231GI50 89 nM 36 nM 17 nMTGI 163 nM 162 nM 136 nMLC50 5,611 nM 732 nM 630 nM
Sensitivity of treatment resistant TNBC cell lines to the anti‐proliferative and cytotoxic effects of TP‐0903 (specific axl inhibitor)
AXL and the immune system1. Efferocytosis induced activation of MERTK in macrophages also promotes the immunosuppressive and wound‐healing (M2) phenotype over the inflammatory (M1) phenotype.
2. AXL is induced following Toll‐like receptor (TLR) signaling in antigen‐presenting cells (APCs) which leads to the suppression of TLR signaling and pro‐inflammatory cytokine release.
3. Activated T cells transcriptionally upregulate vitamin K‐dependent protein S (PROS1) which combined with externalized phosphatidyl serine creates a complex ligand that binds to APCs and suppresses their activity through interaction with TAM receptor tyrosine kinases.
4. TAM RTKs suppresses natural killer (NK) cell function, which promotes enhanced metastasis.
Company Compound Targets Indication Clinical status
Servier S49076(kinase inhibitor)
MET, AXL, FGFR1/2/3 Advanced solid tumors Phase I2013‐003079‐37
Mirati Therapeutics Inc. MGCD516(kinase inhibitor)
MET, AXL, members of VEGFR, PDGFR, DDR2, TRK, and Eph Families
Advanced solid tumors Phase INCT02219711
Mirati Therapeutics Inc. MGCD265(kinase inhibitor)
MET/AXL Advanced malignancies Phase INTC00697632
Betta Pharmaceuticals Co., Ltd
BPI‐9016M(kinase inhibitor)
MET/AXL Advanced solid tumors Phase INCT02478866
BerGenBio AS BGB324(R428; kinase inhibitor)
AXL NSCLC and AML Phase I/IINCT02488408NCT02424617
*ToleroPharmaceuticals
TP‐0903(kinase inhibitor)
AXL Advanced solid tumors Phase INCT02729298
Anti‐AXL agents in clinical development
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A Phase I, First‐in‐human, Open‐label, Dose‐escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP‐0903 Administered Daily for 21 Days to Patients with Advanced Solid Tumors
Misiones San Jose