Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition

Mathilde Couëtoux du Tertre; Maud Marques; Suzan McNamara; Karen Gambaro; Cyrla Hoffert; Lise Tremblay; Nicole Bouchard; Razvan Diaconescu; Normand Blais; Christian Couture; Vincent Pelsser; Hangjun Wang; Laura McIntosh; Valérie Hindie; Stephane Parent; Laetitia Cortes; Yannick-André Breton; Gwenael Pottiez; Pascal Croteau; Valerie Higenell; Luisa Izzi; Alan Spatz; Victor Cohen; Gerald Batist; Jason Agulnik

doi:10.1186/s12014-020-9269-6

Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition

Clin Proteomics. 2020 Feb 7:17:5. doi: 10.1186/s12014-020-9269-6. eCollection 2020.

Authors

Mathilde Couëtoux du Tertre^#^{1

2}, Maud Marques^#^{1

2}, Suzan McNamara^{1

2}, Karen Gambaro^{1

2}, Cyrla Hoffert^{1

2}, Lise Tremblay³, Nicole Bouchard⁴, Razvan Diaconescu⁵, Normand Blais⁶, Christian Couture³, Vincent Pelsser¹, Hangjun Wang¹, Laura McIntosh⁷, Valérie Hindie⁷, Stephane Parent⁷, Laetitia Cortes⁷, Yannick-André Breton⁷, Gwenael Pottiez⁷, Pascal Croteau⁷, Valerie Higenell², Luisa Izzi², Alan Spatz¹, Victor Cohen¹, Gerald Batist^#¹, Jason Agulnik^#¹

Affiliations

¹ Segal Cancer Centre, Jewish General Hospital, McGill University, Jewish General Hospital, 3755, Chemin Cote Ste-Catherine, Montreal, QC H3T1E2 Canada.
² Exactis Innovation, Montréal, QC Canada.
³ 3Institut universitaire de cardiologie et pneumologie de Québec, Université de Laval, Québec, QC Canada.
⁴ 4Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC Canada.
⁵ 5Hopital Sacré-Cœur Montréal, Montréal, QC Canada.
⁶ 6Centre hospitalier universitaire de Montréal, Montréal, QC Canada.
⁷ 7Caprion, Montreal, QC Canada.

^# Contributed equally.

Abstract

Background: ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib.

Methods: Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association.

Results: Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion.

Conclusion: In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy.Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.

Keywords: Crizotinib; Liquid biopsy; NSCLC; Prediction of response; Protein signature.

Associated data

ClinicalTrials.gov/NCT02041468