Cell lineage context and type of genomic alteration predict for the therapeutic relevance of tyrosine kinase inhibitors in human cancers

Abstract

Abstract Background Genomic alterations of receptor tyrosine kinases (RTK) or ligands are biomarkers for some targeted therapies in a fraction of cancers, with heterogeneous responses across tumor types. A general model to predict the efficacy of a targeted treatment in a given tumor type bearing a RTK genomic alteration is lacking. Through database and literature review, we investigated whether the role of a RTK in the normal lineage could predict the response to RTK inhibitors in cancers arising from the same lineage. Methods An analysis of the literature and query of public databases on RTK function in normal cell lineages and neoplastic cells was conducted, for 16 selected RTK (EGFR, HER2, KIT, FLT3, TRKA-B-C, ROS1, ALK, RET, MET, and FGFR1-2-3-4). The physiological role of RTK in the development/maintenance of cell lineages was assessed by looking at the phenotypes resulting from the alteration of the RTK in animal models and/or known human germline mutations. The activity of TKI monotherapy in genomic-driven clinical trials was analyzed through a systematic review of published phase I-II-III studies. Efficacy was defined as a median progression-free survival > 6 months and of a response rate > 30%. A matrix was built to test the association between the physiological role and clinical activity of each RTK according to lineage contexts. Results This analysis reveals a relationship between the role in lineage development and the magnitude of clinical activity of a TKI in a cancer arising from the same lineage. For missense mutations only, the clinical activity was higher when the RTK is involved in the development or maintenance of the normal cell lineage. Conversely, in cancers harboring fusion genes and proteins involving an RTK, TKI were active regardless of cell lineage. Single agent TKI activity was consistently limited in cancers bearing RTK gene amplifications. Conclusions This analysis identifies two preferred genomic biomarkers to select candidate patient for single agent TKI, 1) fusions genes involving an RTK; 2) activating missense mutations in RTK involved in normal cell lineage physiology. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure P.A. Cassier: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Research grant / Funding (institution): Blueprint; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution): Tayo; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Innate. I.L. Ray-Coquard: Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Research grant / Funding (institution): Amgen; Honoraria (self), Research grant / Funding (institution): Genmab; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer. D. Perol: Honoraria (self): AstraZeneca; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Bristol-Myers Squibb. J-Y. Blay: Research grant / Funding (self): PharmaMar; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Novartis; Research grant / Funding (self): Eisai; Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck Sharp and Dohme; Research grant / Funding (self): Bristol-Myers Squibb. All other authors have declared no conflicts of interest.