title: HER2+ Cancer Cell Dependence on PI3K vs. MAPK Signaling Axes Is Determined by Expression of EGFR, ERBB3 and CDKN1B.
abstract: Understanding the molecular pathways by which oncogenes drive cancerous cell growth, and how dependence on such pathways varies between tumors could be highly valuable for the design of anti-cancer treatment strategies. In this work we study how dependence upon the canonical PI3K and MAPK cascades varies across HER2+ cancers, and define biomarkers predictive of pathway dependencies. A panel of 18 HER2+ (ERBB2-amplified) cell lines representing a variety of indications was used to characterize the functional and molecular diversity within this oncogene-defined cancer. PI3K and MAPK-pathway dependencies were quantified by measuring in vitro cell growth responses to combinations of AKT (MK2206) and MEK (GSK1120212; trametinib) inhibitors, in the presence and absence of the ERBB3 ligand heregulin (NRG1). A combination of three protein measurements comprising the receptors EGFR, ERBB3 (HER3), and the cyclin-dependent kinase inhibitor p27 (CDKN1B) was found to accurately predict dependence on PI3K/AKT vs. MAPK/ERK signaling axes. Notably, this multivariate classifier outperformed the more intuitive and clinically employed metrics, such as expression of phospho-AKT and phospho-ERK, and PI3K pathway mutations (PIK3CA, PTEN, and PIK3R1). In both cell lines and primary patient samples, we observed consistent expression patterns of these biomarkers varies by cancer indication, such that ERBB3 and CDKN1B expression are relatively high in breast tumors while EGFR expression is relatively high in other indications. The predictability of the three protein biomarkers for differentiating PI3K/AKT vs. MAPK dependence in HER2+ cancers was confirmed using external datasets (Project Achilles and GDSC), again out-performing clinically used genetic markers. Measurement of this minimal set of three protein biomarkers could thus inform treatment, and predict mechanisms of drug resistance in HER2+ cancers. More generally, our results show a single oncogenic transformation can have differing effects on cell signaling and growth, contingent upon the molecular and cellular context.
authors.affiliation: Discovery, Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Kirouac
authors.affiliation: Discovery, Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.affiliation: Discovery, Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Johanna
authors.initials: J
authors.lastname: Lahdenranta
authors.affiliation: Discovery, Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Onsum
authors.affiliation: Discovery, Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Nielsen
authors.affiliation: Discovery, Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schoeberl
authors.affiliation: Discovery, Merrimack Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Charlotte F
authors.initials: CF
authors.lastname: McDonagh
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D018734:Genes, erbB-2; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C436291:CDKN1B protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human