Article Text
Abstract
Objective Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4.
Design Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens).
Results Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach.
Conclusion This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.
- pancreatic cancer
- extracellular matrix
- molecular mechanisms
- cell cycle
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Footnotes
Contributors Study concept and design (MP, AJG, AC, SJC, PT); data acquisition (AC, DF, AMN, VTC, DW, AP, AS, RS, AD, KJM, JT); analysis and data interpretation (AC, DF, DW, AP, TRC, TJM, JT, CV, KJM, AB, OJS, JM); drafting of manuscript (AC, DF, MP); critical review and edit of manuscript (AJG, PT, AJ, SJC, JS, NW, SMG, LAC, AB, TRC, AVB, TJM, OJS, JM); patient cohort data (APGI, AJ, AVB, JS, AJG, JT, SMG); statistics (AC, MC, MP, DKC); obtained funding (MP, AJG, AC, SJC, PT, JS, AMN, AB, NW); study supervision (MP, AJG).
Funding This work was supported by the National Health and Medical Research Council of Australia (NHMRC) Project Grants 1081312 and 1105640, Cancer Australia Project Grants 1060522 and 1100722 with fellowship support from Cancer Institute NSW, Australian Research Council and NHMRC, scholarship support from NHMRC and Sydney Catalyst and philanthropic support from the Avner Pancreatic Cancer Foundation, The Philip Hemstritch Fellowship in Pancreatic Cancer; Len Ainsworth Pancreatic Cancer Fellowship, Estate of the late RT Hall Cancer Gene Discovery and Validation Program and Norman Green Support Grant.
Competing interests None declared.
Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.
Ethics approval Ethics approval for acquisition of data and biological material was obtained from human research ethics committees from each participating institution (Sydney Local Health District Human Research Ethics Committee X11-0220). In vivo experiments were approved by Garvan/St Vincent’s animal ethics committee (14/11, 14/12).
Provenance and peer review Not commissioned; externally peer reviewed.