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1 Award Number: W8XWH--- TITLE: Defining the Role of Autophagy Kinase ULK Signaling in Therapeutic Response of Tuberous Sclerosis Complex to Inhibitors PRINCIPAL INVESTIGATOR: Reuben J. Shaw, Ph.D. CONTRACTING ORGANIZATION: The Salk Institute for Biological Studies La Jolla, California 97 REPORT DATE: April 5 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 7-5 DISTRIBUTION STATEMENT: X Approved for public release; distribution unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation.
2 REPORT DOCUMENTATION PAGE Form Approved OMB No Public reporting burden for this collection of information is estimated to average hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (7-88), 5 Jefferson Davis Highway, Suite, Arlington, VA -. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS.. REPORT DATE (DD-MM-YYYY) April 5. REPORT TYPE Annual. DATES COVERED (From - To) Apr Mar 5. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Defining the Role of Autophagy Kinase ULK Signaling in Therapeutic Response of Tuberous Sclerosis Complex to Inhibitors 6. AUTHOR(S) Shaw, Reuben J. shaw@salk.edu 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) The Salk Institute for Biological Studies North Torrey Pines Road La Jolla, CA 97-5b. GRANT NUMBER W8XWH--- 5c. PROGRAM ELEMENT NUMBER 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES). SPONSOR/MONITOR S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 7-5. SPONSOR/MONITOR S REPORT NUMBER(S). DISTRIBUTION / AVAILABILITY STATEMENT Approved for public release; distribution unlimited. SUPPLEMENTARY NOTES. ABSTRACT The Tuberous Sclerosis Complex tumor suppressors are known to be critical negative regulators of the C kinase complex that controls growth and. Our laboratory and others have recently decoded a major conserved route that C uses to control. These studies demonstrate that C inactivates another kinase complex composed of the kinase ULK and its associated subunits. One prediction of these findings is that in s and tumors with TSC mutations and hyperactive, the ULK complex and the process of will be suppressed. There were two major aims for this funding period: ) to further develop antibodies and reagents to readout ULK-activity and substrate phosphorylation to see how well they act as biomarkers of inhibition, and ) to further explore use of novel small molecule s of ULK to synergize with s to induce death. 5. SUBJECT TERMS,, ULK, phosphorylation, substrates,, mycin 6. SECURITY CLASSIFICATION OF: 7. LIMITATION OF ABSTRACT a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 8. NUMBER OF PAGES 6 9a. NAME OF RESPONSIBLE PERSON USAMRMC 9b. TELEPHONE NUMBER (include area code) Standard Form 98 (Rev. 8-98) Prescribed by ANSI Std. Z9.8
3 Table of Contents Page Introduction.. Body... Key Research Accomplishments. 6 Reportable Outcomes.. 6 Conclusion 6 References.6 Appendices none
4 XSSOHPHQWDO )LJXUHV FIP with WT ULK A INTRODUCTION FIP with KI ULK The Tuberous Sclerosis Complex tumor suppressors are known to be critical negative regulators of the C kinase complex that controls growth and. Our laboratory and others have recently decoded a major conserved route that C uses to control. These studies demonstrate that C inactivates another kinase complex composed of the kinase ULK and its associated subunits. One prediction of these findings is that in s and tumors with TSC mutations and hyperactive, the ULK complex and the process of will be suppressed. There were two major aims for this funding period: ) to further develop antibodies and reagents to readout ULK-activity and substrate phosphorylation to see how well they act as biomarkers of inhibition, and ) to further explore use of novel small molecule s of ULK to synergize with s to induce death. BODY As Task was accomplished already in year of the funding, in this second year we made significant additional progress on Task,, and 5. Task was aimed at developing reagents to study ULK activity and function, and examine whether they are induced by s as we hypothesized. Task a was aimed at further identifying ULK substrates in vivo whose induction of phosphorylation by ULK may serve as functional biomarkers for inhibition in s. B ATG with KI ULK ATG with WT ULK. In vivo phosphorylation sites were defined in the ULK-binding partner ATG when it was co-expressed with wildc Figure type (WT) or kinase inactive (KI) ULK in HEK9T s. We identified one specific serine in ATG Ser89 that match the 5 against 5 this site. optimal ULK substrate consensus (LxxpSVxx), and are helping develop antibodies Here we have made significant advances, of additional direct substrates that will 5 identifying 5 a number ULK 96 be further summarized in the manuscript we have recently written up about ULK substrates which is Beclin cdna: WT WT WT currently under review Cell. Figure for thewt ULK-binding ULK cdna: - WTat the KI journal WT WTMolecular WT WT WT WT As WTseen WT in WT WT WT WT WT WT protein ATG, only one specific serine amidst the many serines in the protein can serve as a highly phosphorylated direct ULK-phosphorylation sites. The sequence of these sites also conforms to the optimal substrate motif identified above (LxxpSVxx). Task also related to us examining the ULK-dependency of the sites we discovered so we next examined whether we could detect a mobility shift in total ATG protein resolved on an SDS-PAGE gel, which might be indicative of ULK-dependent phosphorylation. To most flag-beclin (phostag) rigorously test this possibility, we examined Atg protein from wild-type and genetically knockout fibroblasts for Ulk and its close family member Ulk and combined treatment of such s with starvation media (EBSS) or catalytic s (INK8, AZD855), with or without use of our new tool compound ULK (see Figure, left). flag-beclin (SDS-PAGE) myc- ULK
5 flag- VPS P-Beclin S5 WT MEF 6965 Ulk/ DKO MEF EBSS INK8 AZD855 56_A59_Settings_55 Event Count: 98 5 nm µm AZD (µm) CQ (µm) Atg Beclin [long exp] pulk S757 [light] Beclin [short exp] pulk S757 [dark] Atg [long exp] D ULK Ulk Atg [short exp] * Beclin Ulk total PARP P-Ulk S757 cleaved S6K p6 p-s6 EBP actin Figure ULK ULK EBP Figure. Examination of ULK targets as biomarkers of inhibition, and validation that our novel compound acts as an ULK. (left) Wild-type or Ulk/Ulk double knockout mouse embryonic fibroblasts (MEFs) (Cheong et al., ) were treated with fresh media (Dulbecco s modified eagle medium containing [DMEM] % fetal bovine serum [FBS]) containing µm INK8, µm AZD855, or or with starvation media (Earle s balanced salt solution [EBSS] in the presence or absence of µm Cellular lysates were isolated after h of treatment and immunoblotted with indicated antibodies. (right) A59 s were treated with, µm INK8, 5 nm mycin, or µm AZD855 in the presence or absence of µm 6965 or µm chloroquine (CQ). Cells were treated for 8 hours and immunoblotted with the indicated antibodies. Actin (Sigma) As seen in in the left panel of Figure, the s induced a modest but reproducible mobility shift in the Beclin and Atg proteins, indicative of increased phosphorylation. This increased mobility was suppressed by treatment with our ULK tool compound ( lanes). No bandshift was seen in the ULK/ DKO MEFs, indicating that these induced biochemical events are blocked by genetic or pharmacological inhibition of ULK. Next we connected these observations towards the main goal of Task and Task 5: to examine the use of ULK s as a therapeutic to combine with s. In these tasks, we proposed to test whether inhibition of ULK can convert cytostatic effects of s into cytotoxic effects. Now that we have a tool compound, Compound 6 (6-695) that shows exent catalytic inhibition towards ULK (see last year s report), we can perform these experiments. As seen in the A59 lung cancer line in the right hand panel of Figure, we examined whether 8h treatment with s with or without ULK triggered caspase activation indicative of death. Indeed the extent of inhibition from INK8 vs AZD855 vs mycin was proportional to the extent of caspase-cleaved PARP (Figure ). This effect was greatest with co-treatment with the ULK than with chloroquine (CQ), which supports our model that inhibition creates a mechanism dependent on ULK. An even more robust biomarker of ULK inhibition in the context of inhibition was the stability of Atg protein, as seen in the right panel of Figure. We therefore propose total Atg protein levels as a biomarker of ULK and synergy. We extended these key goals of this grant by functionally testing the ability of our novel ULK to induce death synergistically with these three different s (Figure ). These findings indicate that our original hypothesis that ULK s will push growth arrested inhibited s into apoptosis holds true, at least in this line. We will now push ahead to test this in the context of TSC-deficiency as proposed for year of this funding. 5 56_A59_Settings_55 Event Count: 775 A59 µm INK8 EBSS AnnexinV C INK8 AZD855 56_A59_Settings_55 Event Count: E P-VPS S9 # Cell # Cell µm AZD855 flag- Beclin Figure 7
6 B A 6965Atg (M) % M % % % 7 Event Count: 58 %.7 6 M INK % Event Count: 6 Event Count: Event Count: Event Count: 68 5 nm AnnexinV A59 % cleaved % %. 8 p6 56_A59_Settings_55 Event Count: 59 % 8 PARP 56_A59_Settings_55 Event Count: _A59_Settings_58 Event Count: 7 total % 56_A59_Settings_59 Event Count: 8 M AZD855 % "#$% Beclin.6 % _A59_Settings_57 Event Count: _A59_Settings_55 Event Count: Ulk 56_A59_Settings_56 Event Count: % 5% 56 5 Event Count: 6 Event Count: _A59_Settings_5 Event Count: pulk S757 [dark] 6 56_A59_Settings_5 Event Count: 5 5% Event Count: 68 M AZD 855 5M 5% 5. 6 M 5% 5. pulk S757 [light] %.9 6 D CQ (M) % (µm) CQ (µm) M AZD855 )LJXUH 5 nm 6 "#$% M INK8 56_A59_Settings_55 Event Count: p-s6 56_A59_Settings_55 Event Count: 98 AnnexinV C 56_A59_Settings_55 Event Count: 775 EBP A59 nm M of 5. Treatment A59 INK8 ULK Figure 7 M Figure lung cancer s with our novel ULK compound with or without s AZD855 (AZD855, INK8, mycin). (A) A59 human lung cancer s were treated with the catalytic AZD855 ( of Cells (µm)were treated for 7 hours and then collected, stained with PE-AnnexinV and µm) or and increasing doses CQ (µm) quantified by FACS analysis. Red numbers indicate the percentage of AnnexinV- positive s, representing s actively D undergoing apoptosis. (B) A59 s wereatg treated with, µm INK8, 5 nm mycin, or µm AZD855 in the presence or absence of µm 6965 or µm chloroquine (CQ). Cells were treated for 8 hours and pulk S757 [light] then collected, stained with PE-AnnexinV and quantified by FACS analysis. pulk S757 [dark] "#$% KEY RESEARCH ACCOMPLISHMENTS Ulk identification of ULK phosphorylation sites in protein to act as biomarkers in vivo Beclin identification of a ULK tool compound that synergizes with s to trigger total death of cancer s PARP cleaved "#$% REPORTABLE OUTCOMES p6 Manuscript submitted to Molecular Cell and currently underulkreview. p-s6 CONCLUSION EBP Figure 7 Our findings during this second year of funding have been very fruitful, accomplishing multiple Tasks as proposed in the Statement of Work of the grant. In particular, we have identified Atg as a ULK substrate in vivo and how shown that Atg total protein levels are an exent biomarker of effective ULK and inhibition. Given the widespread use of s including logs to treat Tuberous Sclerosis Complex, the identified of new biomarkers for TSC treatment is particularly exciting. In addition, we have further characterized our small molecule ATP-competitive s of ULK and our Compound #6-965 behaves as an exent on target of ULK that synergizes converts the cytostatic growth arrest of s starved of s into a cytotoxic death response. We are now testing further how well this compound synergizes with catalytic in TSC-deficient cancer lines and ultimately mouse models, consistent with the aims of the grant proposal here. REFERENCES. Joo, J.H. et al. Hsp9-Cdc7 chaperone complex regulates Ulk- and Atg-mediated mitophagy. Mol Cell, ().. Cheong, H., Lindsten, T., Wu, J., Lu, C. & Thompson, C.B. Ammonia-induced is independent of ULK/ULK kinases. Proc Natl Acad Sci U S A 8, -6 (). 6
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