Abstract 3633
Background
Aurora Kinases (AURK) regulate mitosis and are often upregulated in cancer. SCLC is characterized by TP53 and RB1 loss and frequent MYC amplification. Our group, and others, have proved that MYC-driven SCLC are vulnerable to AURKA-inhibitors (AURKAi), but their use is limited by toxicity due to high AURKA expression. AURKB levels are variable in SCLC, making AURKB an attractive targeted therapeutic approach. A novel AURKBi, AZD2811NP (nanoparticle), is now being investigated in relapsed SCLC patients (NCT02579226). We hypothesize that molecularly defined subsets may be sensitive to AZD2811.
Methods
We tested 50 human-derived SCLC cell lines with AZD2811 in 96 hour proliferation assays. To identify translatable biomarkers of response, we correlated IC50 values with genomic (WES), transcriptomic (RNASeq), and proteomic profiling (RPPA).
Results
AZD2811 is active in a subset of SCLC cells: 13/30 (26%) have high sensitivity (IC50<30 nM, Cmax) and 7/30 (14%) intermediate (IC50=30-100nM). Comparing protein expression, we found that cMYC (Fold change, FC:2.5; P = 0.015) and Vimentin (FC:1.66; P = 0.022) were top biomarkers of sensitivity, while high E-cadherin (FC:1.94; P = 0.046) and BCL-2 (FC:1.86; P = 0.032) associated with resistance. Interestingly, among the 13 highly sensitive cells, only 5 overexpress cMYC, highlighting that activity of AURKBi is not limited to MYC-driven SCLC. Indeed, among recently-described transcription factor defined subsets of SCLC, a majority of the NEUROD1-defined subset (cMYC enriched) were sensitive to AZD2811, as 25% of ASCL1- and 67% of POU2F-3-defined ones. These data suggest that the ASCL1 subset includes heterogeneous sub-groups that require further analysis to dissect their molecular features. Mutations in EP300, a Histone acetyltransferase that controls chromatin modification and transcription, also predict sensitivity.
Conclusions
Our results show encouraging single agent in vitro activity of AZD2811 in SCLC cells, and suggest a novel biomarker-driven approach for combinations. Candidate biomarkers will be tested in samples from the ongoing clinical trial. The high BCL2 levels observed in resistant cells provide a rationale for exploring AURKB/BCL2-i combinations.
Clinical trial identification
NCT02579226.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
AstraZeneca.
Disclosure
C.A. Adelman: Full / Part-time employment: AstraZeneca. J. Travers: Full / Part-time employment: AstraZeneca. J. Heymach: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Licensing / Royalties: BioTree; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Genentech; Advisory / Consultancy: GSK; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Hengrui; Advisory / Consultancy: Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self), Licensing / Royalties: Spectrum; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Synta; Research grant / Funding (self): Bayer; Research grant / Funding (self): GlaxoSmithKline. L.A. Byers: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): GenMab; Advisory / Consultancy: BergenBio; Advisory / Consultancy: Pharma Mar; Advisory / Consultancy: SA; Advisory / Consultancy, Research grant / Funding (self): Sierra Oncology; Research grant / Funding (self): Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.
Resources from the same session
5054 - Inhibition of Rspo-Wnt pathway Facilitates Checkpoint Blockade Therapy by anti-RSPO3 antibody (DBPR117)
Presenter: John Hsu
Session: Poster Display session 1
Resources:
Abstract
3305 - A phase I dose-escalation and expansion trial of intratumorally administered CV8102, alone and in combination with anti-PD-1 in patients with advanced solid tumors
Presenter: Jürgen Krauss
Session: Poster Display session 1
Resources:
Abstract
5353 - Phase 1/2 Study of 9-ING-41, a small molecule selective Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined with Chemotherapy, in Patients with Refractory Hematological Malignancies or Solid Tumors
Presenter: Benedito Carneiro
Session: Poster Display session 1
Resources:
Abstract
3946 - Trial in progress: a Phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumors (NCT03447314).
Presenter: Aaron Hansen
Session: Poster Display session 1
Resources:
Abstract
3449 - Radiographic Phenotyping to Identify Intracranial Disseminated Recurrence in Brain metastases Treated With Radiosurgery Using Contrast-enhanced MR Imaging
Presenter: CheYu Hsu
Session: Poster Display session 1
Resources:
Abstract
4553 - Association between TP53 mutations and efficacy of Osimertinib for brain metastasis from EGFR-mutant lung cancer
Presenter: Lijuan Chen
Session: Poster Display session 1
Resources:
Abstract
4942 - Response assessment of melanoma brain metastases treated by stereotactic radiotherapy or immunotherapy or both: a comparison of RECIST 1.1, RANO and iRANO criteria
Presenter: Emilie Le Rhun
Session: Poster Display session 1
Resources:
Abstract
3529 - Management of multiple brain metastases by Staged SRS focusing on utmost risk lesions
Presenter: shaoqun Li
Session: Poster Display session 1
Resources:
Abstract
5315 - Whole brain radiotherapy plus simultaneous in-field boost versus whole brain radiotherapy plus fractionated stereotactic radiotherapy for multiple brain metastases of non-small cell lung cancer
Presenter: Lu Li
Session: Poster Display session 1
Resources:
Abstract
1116 - 3D based texture analysis serving as potential diagnostic factor in discriminating primary central nervous system lymphoma from metastatic brain tumors: A preliminary study
Presenter: Wen Guo
Session: Poster Display session 1
Resources:
Abstract