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
5519 - Is there a difference of Palliative care problems and needs between cancer and non-cancer hospitalized elderly patients?
Presenter: Ioanna Chatzi
Session: Poster Display session 1
Resources:
Abstract
2505 - There is a lack of clinical research for patients with cancer in palliative care
Presenter: Marie Vinches
Session: Poster Display session 1
Resources:
Abstract
5273 - Specialist Palliative Care (SPC) in Haematological Malignancy: Establishing practices in a UK Tertiary Cancer Centre (TCC)
Presenter: Emma Kedgley
Session: Poster Display session 1
Resources:
Abstract
5864 - Evaluation of the relationship between the attachment styles and psychological resilience of cancer patients receiving chemotherapy
Presenter: Fatma Bugdayci Basal
Session: Poster Display session 1
Resources:
Abstract
770 - Gefitinib along with Methotrexate as palliative therapy in PS 3 and above in metastatic squamous cell carcinoma head and neck cancer patients
Presenter: Vidya Dusi
Session: Poster Display session 1
Resources:
Abstract
4232 - High intensity end-of-life care in pediatrics, adolescent and young adult patients with cancer using an administrative database.
Presenter: Seiko Bun
Session: Poster Display session 1
Resources:
Abstract
4845 - Embedded outpatient palliative care service within the oncology clinic: Preliminary experience in Hacettepe Oncology Hospital
Presenter: Deniz Can Guven
Session: Poster Display session 1
Resources:
Abstract
3270 - Internet-based stepped care for individuals with cancer and concurrent anxiety or depression symptoms – results from a randomized controlled trial
Presenter: Birgitta Johansson
Session: Poster Display session 1
Resources:
Abstract
5503 - Impact of Cognitive-Behavioral-Therapy (CBT) on levels of anxiety, depression and distress in cancer patients (pts)
Presenter: Daniela Tregnago
Session: Poster Display session 1
Resources:
Abstract
5553 - Cytokine genetic variations and worse quality of life among family caregivers of head and neck cancer patients in palliative care
Presenter: Daniel Pequeno
Session: Poster Display session 1
Resources:
Abstract