Gwenda F. Ligon 1, Jay S. Lillquist 1, Edward J. Natoli Jr

Slides:



Advertisements
Similar presentations
Inhibition of Poly (ADP-Ribose) Polymerase (PARP) by ABT-888 in Patients With Advanced Malignancies: Results of a Phase 0 Trial Shivaani Kummar, MD National.
Advertisements

Moskowitz CH et al. Proc ASH 2014;Abstract 290.
MiRNA-drug resistance mechanisms Summary Hypothesis: The interplay between miRNAs, signaling pathways and epigenetic and genetic alterations are responsible.
Title, in bold style Subtitle, in regular Max 3 lines of text totally NB! The graphic outside the slide will not show in “Slide Show” or on print WntResearch.
Efficacy and Safety of Conatumumab Plus AMG 479 in Patients With Advanced Sarcoma S Chawla,1 AC Lockhart,2 N Azad,3 E Elez,4 F Galimi,5 N Baker,6 YJ.
Detection of Mutations in EGFR in Circulating Lung-Cancer Cells Colin Reisterer and Nick Swenson S. Maheswaran et al. The New England Journal of Medicine.
Phase 1/2 Study of GSK , a Selective Inhibitor of Oncogenic Mutant BRAF Kinase in Patients with Metastatic Melanoma and Other Solid Tumors Kefford.
New Developments in Cancer Treatment Dulcinea Quintana, MD.
Advanced Cancer Topics Journal Review 4/16/2009 AD.
Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) in Non-Small Cell Lung Cancer (NSCLC) Victor.
Activity and Tolerability of Afatinib (BIBW 2992) and Cetuximab in NSCLC Patients with Acquired Resistance to Erlotinib or Gefitinib Janjigian YY et al.
Final Efficacy Results from OAM4558g, a Randomized Phase II Study Evaluating MetMAb or Placebo in Combination with Erlotinib in Advanced NSCLC Spigel DR.
Cortés J et al. ASCO 2009; Abstract (Poster Discussion)
Company Highlights Legacy of creating and developing drugs that have transformed patient care Expansive and rapidly advancing portfolio of novel and differentiated.
Progress in Cancer Therapy Following Developments in Biopharma
Mothaffar F. Rimawi, Ingrid A. Mayer, Andres Forero, Rita Nanda, Matthew P. Goetz, Angel A. Rodriguez, Anne C. Pavlick, Tao Wang, Susan G. Hilsenbeck,
01/22/2010 – 7:45pmeSlide – P6617 – MedImmune 4 x 8 Poster Template Detection of a human anti-PDGFR  therapeutic antibody in a human GBM orthotopic rat.
Esophageal Cancer: A Critical Evaluation of Systemic Second-Line Therapy Christiane Maria Rosina Thallinger, Markus Raderer, and Michael Hejna J Clin Oncol.
KEYNOTE-021: Pembrolizumab + Ipilimumab Active in Previously Treated Advanced NSCLC CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting*
Vice President, Cancer Therapeutics, Inc.
EGFR exon 20 insertion mutations
Recent Advances in NSCLC Treatment
Defining Epidermal Growth Factor Receptor exon 20 mutant sensitivity to tyrosine kinase inhibition Danny Rayes.
Samsung Genome Institute Samsung Medical Center
Wolfram C. M. Dempke SaWo Oncology Ltd May 13, 2017
CCO Independent Conference Highlights
PI3K inhibition does not Effect the BH3 Profile of SW620 Cells
Ramucirumab Protein chemical formula : C6374H9864N1692O1996S46
Nivolumab Drugbank ID : DB09035 Molecular Weight (Daltons) :
Pembrolizumab Drugbank ID :DB09037 Half life : 28 days.
Cetuximab Drugbank ID : DB00002
Figure 1. Resistance mechanism against first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). (A) Mutations in the EGFR.
Nivolumab in Patients (Pts) with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL): Clinical Outcomes from Extended Follow-up of a Phase 1 Study.
Suzanne L. Topalian, Charles G. Drake, Drew M. Pardoll  Cancer Cell 
A new therapeutic antibody masks ErbB2 to its partners
Combined Inhibition of PD-L1, MEK, and BRAF Active in Advanced Melanoma CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 -
Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth
Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR- Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients.
Combined RAF and EGFR inhibition leads to improved in vivo efficacy in BRAF-mutant colorectal cancer. Combined RAF and EGFR inhibition leads to improved.
MAPK pathway inhibitors.
Volume 134, Issue 4, Pages (April 2008)
Carlos L. Arteaga, Jeffrey A. Engelman  Cancer Cell 
Latest Advances in Chemotherapeutic, Targeted, and Immune Approaches in the Treatment of Metastatic Melanoma  Darshil J. Shah, MD, MPH, Roxana S. Dronca,
Figure 1 A schematic representation of the HER2 signalling pathway
Activity Goals. Activity Goals Program Overview.
On the TRAIL to Overcome BRAF-Inhibitor Resistance
EGFR T790M Mutation: A Double Role in Lung Cancer Cell Survival?
Volume 10, Issue 6, Pages (December 2004)
A new therapeutic antibody masks ErbB2 to its partners
RESEARCH IN MOLECULAR THERAPI
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism by Piro Lito, Martha Solomon, Lian-Sheng Li, Rasmus Hansen, and Neal Rosen.
Volume 22, Issue 6, Pages (December 2012)
- Phase 1 Signalling Study
HIV Drug to Aid Melanoma Therapies?
Volume 10, Issue 1, Pages (July 2006)
The RAF Inhibitor Paradox Revisited
William G. Nelson, Michael C. Haffner, Srinivasan Yegnasubramanian 
Genetics of Langerhance Cell Histiocytosis
MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway
Volume 22, Issue 5, Pages (November 2012)
Molecular Characterization of Acquired Resistance to the BRAF Inhibitor Dabrafenib in a Patient with BRAF-Mutant Non–Small-Cell Lung Cancer  Charles M.
Mutant BRAF Melanomas—Dependence and Resistance
Clinical response to anti-ERBB3 mAb therapy in a patient with an advanced NRG1-rearranged non–small cell lung cancer. Clinical response to anti-ERBB3 mAb.
Volume 2, Issue 2, Pages (August 2002)
A Molecular View of Anti-ErbB Monoclonal Antibody Therapy
Successful targeting of ErbB2 receptors—is PTEN the key?
PTEN and p53: Who will get the upper hand?
Cell-autonomous mechanisms of resistance to targeted therapies involving the HGF/MET axis. Cell-autonomous mechanisms of resistance to targeted therapies.
Therapeutic strategies for different classes of BRAF and MEK mutations
Presentation transcript:

ErbB3 Upregulation as a Mechanism of Resistance to BRAF/MEK Inhibitors in the BRAF Mutant Setting Gwenda F. Ligon 1, Jay S. Lillquist 1, Edward J. Natoli Jr. 1, Jennifer A. Pendleton 1, Ada M. Vaill 1, Andrew R. Proffitt, Christine K. Lubeski 1 J. Paul Eder 2, Carolyn F. Sidor 1, Ronald A. Peck 1, Theresa M. LaVallee 1, Diego Alvarado 1 Kolltan Pharmaceuticals, Inc., New Haven, CT 1; Yale Cancer Center, New Haven, CT 2 Introduction Results KTN3379 is an IgG1 monoclonal antibody against ErbB3 that inhibits both ligand-dependent and –independent activation. Three point mutations (YTE) in the Fc region of KTN3379 should increase antibody serum half-life through enhanced affinity to FcRN. ErbB3 is a kinase-dead member of the ErbB family that functions as an obligate heterodimer with other ErbB receptors. ErbB3 activation is mediated by its cognate ligand neuregulin/heregulin (NRG/HRG), or in the absence of ligand where ErbB2 is overexpressed. ErbB3 provides strong pro-survival signals in solids tumors by engaging the PI3K/AKT signaling pathway. ErbB3 upregulation may drive resistance to targeted therapies ErbB3 Upregulation upon BRAF/MEK Inhibition in BRAF Mutant Cell Lines NRG1 and NRG2 are Highly Expressed in BRAF Mutated Thyroid Cancer and Melanoma, Respectively NRG1 and NRG2 RNA expression was surveyed in different BRAF mutated tumor types NRG1 is highly expressed in thyroid cancer, whereas NRG2 is highly expressed in melanoma Ongoing Phase 1b Evaluation of KTN3379 Combinations in Selected Tumors Dose Escalation in refractory advanced cancer patients 3 + 3 Design 5, 10, 20 mg/kg (Complete n = 14) 15 mg/kg or 1200 mg N=6 Every 3 weeks Safety PK, PD, MTD Cetuximab Head & Neck, Colorectal Erlotinib NSCLC Vemurafenib BRAF Mutant Melanoma, Lung, CRC, Thyroid, etc Trastuzumab Her2+ Breast Cancer, Esophageal KTN3379 Combination KTN3379 Locks ErbB3 in its Autoinhibited Conformation KTN3379 binds to the hinge region between domains 2 and 3 and stabilizes ErbB3 in its inactive conformation Lee S. et al. 2015. PNAS Although the antibody does not bind to the ligand binding site, it allosterically precludes NRG binding to ErbB3. Treatment of BRAF mutated cell lines with trametinib or vemurafenib for 24 hours results in cell-surface upregulation of ErbB3, as determined with an anti-ErbB3 antibody (left), or fluorescently-labeled NRG1 (right). D3 D4 D2 D1 Fab3379 VL BRAF/MEK Inhibition Sensitizes Mutant Cell Lines to ErbB3/NRG Signaling NRG1 and NRG2 Expression is Highly Prevalent in Thyroid Cancer and Melanoma, Respectively Preliminary Results (Bauer et al ASCO 2015 abstr 2598) MTD not established with KTN3379 monotherapy up to maximum administered dose of 20 mg/kg Most common toxicities for KTN3379 alone or in combination have included diarrhea and rash KTN3379 can be combined with vemurafenib, cetuximab, erlotinib, trastuzumab at 15 to 20 mg/kg Q3W All patients achieved serum concentrations above those required for maximal antitumor activity in animal tumor models Pharmacodynamic biomarker analyses showed soluble circulating ErbB3 levels were increased in all patients at all doses Enrollment continues in the four phase 1b cohorts Preliminary tumor response (NSCLC, CRC) data support Phase 2 studies in BRAF mutant cancers and other settings (eg., Head & Neck cancer) TMA: tumor microarray BRAF mutation frequency: - Thyroid: 40-50% - Melanoma: ~50% Titration of trametinib or vemurafenib for 24 hours on BRAF mutated cell lines results in potent upregulation of NRG-induced ErbB3 and AKT phosphorylation relative to untreated samples Conclusions NRG1b is a More Potent ErbB3 Agonist than NRG1a, NRG2a or NRG2b NRG Rescues and KTN3379 Resensitizes Cells to the Antiproliferative Effects of BRAF/MEK Inhibition KTN3379 Inhibits ErbB3 Irrespective of its Mechanism of Activation Targeting ErbB3 with KTN3379 hampers adaptive resistance to BRAF/MEK inhibitors in tumors with an oncogenic MAPK signaling drive. ErbB3 is upregulated in response to BRAF/MEK inhibition. NRG-stimulated activation of ErbB3 and AKT is potentiated dose dependently with trametinib or vemurafenib treatment of BRAF mutant tumor cell lines. NRG attenuates the antiproliferative effects of BRAF/MEK inhibitiors, however treatment with KTN3379 resensitizes the tumor cells to inhibitors. Tumors with a high prevalence of BRAF mutation express NRG1 (thyroid) and/or NRG2 (melanoma) which may provide autocrine stimulation of ErbB3 and contribute to adaptive resistance to BRAF/MEK inhibitors. NRG1b is the most potent ErbB3 ligand tested. An ongoing Phase 1b study combining KTN3379 with vemurafenib in BRAF mutated tumors support further development in BRAF mutant cancer and other settings (eg., Head & Neck cancer) NRG-dependent setting 1a 1b 2a 2b NRG KDa 50 37 25 HER2-amplified setting The full extracellular domains of the two major NRG1 and NRG2 isoforms were secreted from HEK-293 cells, purified and used to stimulate ErbB3 phosphorylation in T47D cells NRG1b activates ErbB3 with an approximately 10-fold greater potency than the other NRG species. ErbB3 exists in an equilibrium between a tethered and and extended state (left). NRG stabilizes the extended conformation of ErbB3 promoting heterodimerization and subsequent activation (top panel). In ErbB2-overexpressing tumors, ErbB3 can be activated independent of ligand (bottom panel). By blocking ErbB3 at the first step of activation, KTN3379 can inhibit either mode of ErbB3 activation. NRG attenuates the antiproliferative activity of trametinib and vemurafenib.