CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance

Kang Seo Park, Mark Raffeld, Yong Wha Moon, Liqiang Xi, Caterina Bianco, Trung Pham, Liam C. Lee, Tetsuya Mitsudomi, Yasushi Yatabe, Isamu Okamoto, Deepa Subramaniam, Tony Mok, Rafael Rosell, Ji Luo, David S. Salomon, Yisong Wang, Giuseppe Giaccone

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Abstract

The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.

Original languageEnglish
Pages (from-to)3003-3015
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
Publication statusPublished - Jul 1 2014
Externally publishedYes

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Non-Small Cell Lung Carcinoma
MicroRNAs
Epithelial-Mesenchymal Transition
Protein-Tyrosine Kinases
Mutation
Erlotinib Hydrochloride
Epidermal Growth Factor
Heterografts
Neoplasms
Down-Regulation
Growth
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Park, K. S., Raffeld, M., Moon, Y. W., Xi, L., Bianco, C., Pham, T., ... Giaccone, G. (2014). CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance. Journal of Clinical Investigation, 124(7), 3003-3015. https://doi.org/10.1172/JCI73048

CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance. / Park, Kang Seo; Raffeld, Mark; Moon, Yong Wha; Xi, Liqiang; Bianco, Caterina; Pham, Trung; Lee, Liam C.; Mitsudomi, Tetsuya; Yatabe, Yasushi; Okamoto, Isamu; Subramaniam, Deepa; Mok, Tony; Rosell, Rafael; Luo, Ji; Salomon, David S.; Wang, Yisong; Giaccone, Giuseppe.

In: Journal of Clinical Investigation, Vol. 124, No. 7, 01.07.2014, p. 3003-3015.

Research output: Contribution to journalArticle

Park, KS, Raffeld, M, Moon, YW, Xi, L, Bianco, C, Pham, T, Lee, LC, Mitsudomi, T, Yatabe, Y, Okamoto, I, Subramaniam, D, Mok, T, Rosell, R, Luo, J, Salomon, DS, Wang, Y & Giaccone, G 2014, 'CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance', Journal of Clinical Investigation, vol. 124, no. 7, pp. 3003-3015. https://doi.org/10.1172/JCI73048
Park, Kang Seo ; Raffeld, Mark ; Moon, Yong Wha ; Xi, Liqiang ; Bianco, Caterina ; Pham, Trung ; Lee, Liam C. ; Mitsudomi, Tetsuya ; Yatabe, Yasushi ; Okamoto, Isamu ; Subramaniam, Deepa ; Mok, Tony ; Rosell, Rafael ; Luo, Ji ; Salomon, David S. ; Wang, Yisong ; Giaccone, Giuseppe. / CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 7. pp. 3003-3015.
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abstract = "The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.",
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AU - Bianco, Caterina

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AU - Lee, Liam C.

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AU - Subramaniam, Deepa

AU - Mok, Tony

AU - Rosell, Rafael

AU - Luo, Ji

AU - Salomon, David S.

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AU - Giaccone, Giuseppe

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