A pilot characterization of human lung NSCLC by protein pathway activation mapping

Angela Zupa, Giuseppina Improta, Alessandra Silvestri, Elisa Pin, Jianghong Deng, Michele Aieta, Pellegrino Musto, Donato Nitti, Enzo Mammano, Lance Liotta, Claudio Belluco, Julia Wulfkuhle, Emanuel Petricoin

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

BACKGROUND:: An understanding of the activated protein signaling architecture in non-small-cell lung cancer (NSCLC) is of critical importance to the development of new therapeutic approaches and identification of predictive and prognostic biomarkers for patient stratification. METHODS:: We used reverse-phase protein microarrays to map the activated protein signaling networks of 47 NSCLC tumors, 28 of which were node negative, which were subjected to tumor cellular enrichment using laser capture microdissection. The phosphorylation/cleavage levels of 111 key signaling proteins and total levels of 17 proteins were measured for broadscale signaling analysis. RESULTS:: Pathway activation mapping of NSCLC revealed distinct subgroups composed of epidermal growth factor receptor (ERBB1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4), v-akt murine thymoma viral oncogene homolog 1- mammalian target of rapamycin (AKT-mTOR), protein kinase, AMP-activated, alpha 2 catalytic subunit (AMPK), and autophagy-related signaling, along with transforming growth factor-beta-signaling protein 1 (SMAD), insulin-line growth factor receptor (IGFR), rearranged during transfection proto-oncogene (RET), and activated CDC42-associated kinase (ACK) activation. Investigation of epidermal growth factor receptor (EGFR)-driven signaling identified a unique cohort of tumors with low EGFR protein expression yet high relative levels of phosphorylated EGFR and high EGFR total protein with low relative levels of phosphorylation. Last, mapping analysis of patients with NSCLC with N0 disease revealed a pilot pathway activation signature composed of linked epidermal growth factor receptor family (HER)-AMPK-AKT-mTOR signaling network along with focal adhesion kinase- LIM domain kinase-1 (FAK-LIMK) and janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways that correlated with short-term survival and aggressive disease. CONCLUSIONS:: Functional protein pathway activation mapping of NSCLC reveals distinct activation subgroups that are underpinned by important therapeutic targets and that patients with early-stage node negative disease and poor prognosis may be identified by activation of defined, biochemically linked protein signaling events. Such findings, if confirmed in larger study sets, could help select and stratify patients for personalized targeted therapies.

Original languageEnglish
Pages (from-to)1755-1766
Number of pages12
JournalJournal of Thoracic Oncology
Volume7
Issue number12
DOIs
Publication statusPublished - Dec 2012

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Non-Small Cell Lung Carcinoma
Epidermal Growth Factor Receptor
Lung
Oncogenes
Proteins
Leukemia
AMP-Activated Protein Kinases
Janus Kinase 1
Lim Kinases
TOR Serine-Threonine Kinases
Phosphorylation
Laser Capture Microdissection
Focal Adhesion Protein-Tyrosine Kinases
Neoplasms
Protein Array Analysis
Thymoma
Growth Factor Receptors
Proto-Oncogenes
Autophagy
Sirolimus

Keywords

  • Cell signaling
  • Non-small-cell lung cancer
  • Protein pathway activation mapping
  • Reverse-phase protein microarrays

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

A pilot characterization of human lung NSCLC by protein pathway activation mapping. / Zupa, Angela; Improta, Giuseppina; Silvestri, Alessandra; Pin, Elisa; Deng, Jianghong; Aieta, Michele; Musto, Pellegrino; Nitti, Donato; Mammano, Enzo; Liotta, Lance; Belluco, Claudio; Wulfkuhle, Julia; Petricoin, Emanuel.

In: Journal of Thoracic Oncology, Vol. 7, No. 12, 12.2012, p. 1755-1766.

Research output: Contribution to journalArticle

Zupa, A, Improta, G, Silvestri, A, Pin, E, Deng, J, Aieta, M, Musto, P, Nitti, D, Mammano, E, Liotta, L, Belluco, C, Wulfkuhle, J & Petricoin, E 2012, 'A pilot characterization of human lung NSCLC by protein pathway activation mapping', Journal of Thoracic Oncology, vol. 7, no. 12, pp. 1755-1766. https://doi.org/10.1097/JTO.0b013e3182725fc7
Zupa, Angela ; Improta, Giuseppina ; Silvestri, Alessandra ; Pin, Elisa ; Deng, Jianghong ; Aieta, Michele ; Musto, Pellegrino ; Nitti, Donato ; Mammano, Enzo ; Liotta, Lance ; Belluco, Claudio ; Wulfkuhle, Julia ; Petricoin, Emanuel. / A pilot characterization of human lung NSCLC by protein pathway activation mapping. In: Journal of Thoracic Oncology. 2012 ; Vol. 7, No. 12. pp. 1755-1766.
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abstract = "BACKGROUND:: An understanding of the activated protein signaling architecture in non-small-cell lung cancer (NSCLC) is of critical importance to the development of new therapeutic approaches and identification of predictive and prognostic biomarkers for patient stratification. METHODS:: We used reverse-phase protein microarrays to map the activated protein signaling networks of 47 NSCLC tumors, 28 of which were node negative, which were subjected to tumor cellular enrichment using laser capture microdissection. The phosphorylation/cleavage levels of 111 key signaling proteins and total levels of 17 proteins were measured for broadscale signaling analysis. RESULTS:: Pathway activation mapping of NSCLC revealed distinct subgroups composed of epidermal growth factor receptor (ERBB1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4), v-akt murine thymoma viral oncogene homolog 1- mammalian target of rapamycin (AKT-mTOR), protein kinase, AMP-activated, alpha 2 catalytic subunit (AMPK), and autophagy-related signaling, along with transforming growth factor-beta-signaling protein 1 (SMAD), insulin-line growth factor receptor (IGFR), rearranged during transfection proto-oncogene (RET), and activated CDC42-associated kinase (ACK) activation. Investigation of epidermal growth factor receptor (EGFR)-driven signaling identified a unique cohort of tumors with low EGFR protein expression yet high relative levels of phosphorylated EGFR and high EGFR total protein with low relative levels of phosphorylation. Last, mapping analysis of patients with NSCLC with N0 disease revealed a pilot pathway activation signature composed of linked epidermal growth factor receptor family (HER)-AMPK-AKT-mTOR signaling network along with focal adhesion kinase- LIM domain kinase-1 (FAK-LIMK) and janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways that correlated with short-term survival and aggressive disease. CONCLUSIONS:: Functional protein pathway activation mapping of NSCLC reveals distinct activation subgroups that are underpinned by important therapeutic targets and that patients with early-stage node negative disease and poor prognosis may be identified by activation of defined, biochemically linked protein signaling events. Such findings, if confirmed in larger study sets, could help select and stratify patients for personalized targeted therapies.",
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AU - Improta, Giuseppina

AU - Silvestri, Alessandra

AU - Pin, Elisa

AU - Deng, Jianghong

AU - Aieta, Michele

AU - Musto, Pellegrino

AU - Nitti, Donato

AU - Mammano, Enzo

AU - Liotta, Lance

AU - Belluco, Claudio

AU - Wulfkuhle, Julia

AU - Petricoin, Emanuel

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N2 - BACKGROUND:: An understanding of the activated protein signaling architecture in non-small-cell lung cancer (NSCLC) is of critical importance to the development of new therapeutic approaches and identification of predictive and prognostic biomarkers for patient stratification. METHODS:: We used reverse-phase protein microarrays to map the activated protein signaling networks of 47 NSCLC tumors, 28 of which were node negative, which were subjected to tumor cellular enrichment using laser capture microdissection. The phosphorylation/cleavage levels of 111 key signaling proteins and total levels of 17 proteins were measured for broadscale signaling analysis. RESULTS:: Pathway activation mapping of NSCLC revealed distinct subgroups composed of epidermal growth factor receptor (ERBB1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4), v-akt murine thymoma viral oncogene homolog 1- mammalian target of rapamycin (AKT-mTOR), protein kinase, AMP-activated, alpha 2 catalytic subunit (AMPK), and autophagy-related signaling, along with transforming growth factor-beta-signaling protein 1 (SMAD), insulin-line growth factor receptor (IGFR), rearranged during transfection proto-oncogene (RET), and activated CDC42-associated kinase (ACK) activation. Investigation of epidermal growth factor receptor (EGFR)-driven signaling identified a unique cohort of tumors with low EGFR protein expression yet high relative levels of phosphorylated EGFR and high EGFR total protein with low relative levels of phosphorylation. Last, mapping analysis of patients with NSCLC with N0 disease revealed a pilot pathway activation signature composed of linked epidermal growth factor receptor family (HER)-AMPK-AKT-mTOR signaling network along with focal adhesion kinase- LIM domain kinase-1 (FAK-LIMK) and janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways that correlated with short-term survival and aggressive disease. CONCLUSIONS:: Functional protein pathway activation mapping of NSCLC reveals distinct activation subgroups that are underpinned by important therapeutic targets and that patients with early-stage node negative disease and poor prognosis may be identified by activation of defined, biochemically linked protein signaling events. Such findings, if confirmed in larger study sets, could help select and stratify patients for personalized targeted therapies.

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