Radiation resistance in KRAS-mutated lung cancer is enabled by stem-like properties mediated by an osteopontin-EGFR pathway

Meng Wang; Jing Han; Lynnette Marcar; Joshua C. Black; Qi Liu; Xiangyong Li; Kshithija Nagulapalli; Lecia V. Sequist; Raymond H. Mak; Cyril H. Benes; Theodore S. Hong; Kristin Gurtner; Mechthild Krause; Michael Baumann; Jing X. Kang; Johnathan R. Whetstine; Henning Willers

doi:10.1158/0008-5472.CAN-16-0808

Radiation resistance in KRAS-mutated lung cancer is enabled by stem-like properties mediated by an osteopontin-EGFR pathway

Meng Wang, Jing Han, Lynnette Marcar, Joshua C. Black, Qi Liu, Xiangyong Li, Kshithija Nagulapalli, Lecia V. Sequist, Raymond H. Mak, Cyril H. Benes, Theodore S. Hong, Kristin Gurtner, Mechthild Krause, Michael Baumann, Jing X. Kang, Johnathan R. Whetstine, Henning Willers

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

Abstract

Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here, we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA doublestrand breaks and repressed putative negative regulators of stem-like properties, such as CRMP1 and BIM. The MLCCpositive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers, with possible implications for prognostic and therapeutic strategies.

Original language	English
Pages (from-to)	2018-2028
Number of pages	11
Journal	Cancer Research
Volume	77
Issue number	8
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-0808
State	Published - Apr 15 2017

Keywords

A549 Cells
Animals
Carcinoma, Non-Small-Cell Lung/genetics
ErbB Receptors/metabolism
Female
Heterografts
Humans
Lung Neoplasms/genetics
Male
Mice
Mice, Nude
Mutation
Neoplastic Stem Cells/metabolism
Osteopontin/biosynthesis
Proto-Oncogene Proteins p21(ras)/genetics
Radiation Tolerance/genetics
Signal Transduction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/0008-5472.CAN-16-0808

Cite this

Wang, M., Han, J., Marcar, L., Black, J. C., Liu, Q., Li, X., Nagulapalli, K., Sequist, L. V., Mak, R. H., Benes, C. H., Hong, T. S., Gurtner, K., Krause, M., Baumann, M., Kang, J. X., Whetstine, J. R., & Willers, H. (2017). Radiation resistance in KRAS-mutated lung cancer is enabled by stem-like properties mediated by an osteopontin-EGFR pathway. Cancer Research, 77(8), 2018-2028. https://doi.org/10.1158/0008-5472.CAN-16-0808

@article{5f2badb2dfed4ae3ad1a59f2dff38753,

title = "Radiation resistance in KRAS-mutated lung cancer is enabled by stem-like properties mediated by an osteopontin-EGFR pathway",

abstract = "Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here, we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA doublestrand breaks and repressed putative negative regulators of stem-like properties, such as CRMP1 and BIM. The MLCCpositive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers, with possible implications for prognostic and therapeutic strategies.",

keywords = "A549 Cells, Animals, Carcinoma, Non-Small-Cell Lung/genetics, ErbB Receptors/metabolism, Female, Heterografts, Humans, Lung Neoplasms/genetics, Male, Mice, Mice, Nude, Mutation, Neoplastic Stem Cells/metabolism, Osteopontin/biosynthesis, Proto-Oncogene Proteins p21(ras)/genetics, Radiation Tolerance/genetics, Signal Transduction",

author = "Meng Wang and Jing Han and Lynnette Marcar and Black, {Joshua C.} and Qi Liu and Xiangyong Li and Kshithija Nagulapalli and Sequist, {Lecia V.} and Mak, {Raymond H.} and Benes, {Cyril H.} and Hong, {Theodore S.} and Kristin Gurtner and Mechthild Krause and Michael Baumann and Kang, {Jing X.} and Whetstine, {Johnathan R.} and Henning Willers",

note = "Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",

year = "2017",

month = apr,

day = "15",

doi = "10.1158/0008-5472.CAN-16-0808",

language = "English",

volume = "77",

pages = "2018--2028",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "8",

}

Wang, M, Han, J, Marcar, L, Black, JC, Liu, Q, Li, X, Nagulapalli, K, Sequist, LV, Mak, RH, Benes, CH, Hong, TS, Gurtner, K, Krause, M, Baumann, M, Kang, JX, Whetstine, JR & Willers, H 2017, 'Radiation resistance in KRAS-mutated lung cancer is enabled by stem-like properties mediated by an osteopontin-EGFR pathway', Cancer Research, vol. 77, no. 8, pp. 2018-2028. https://doi.org/10.1158/0008-5472.CAN-16-0808

TY - JOUR

T1 - Radiation resistance in KRAS-mutated lung cancer is enabled by stem-like properties mediated by an osteopontin-EGFR pathway

AU - Wang, Meng

AU - Han, Jing

AU - Marcar, Lynnette

AU - Black, Joshua C.

AU - Liu, Qi

AU - Li, Xiangyong

AU - Nagulapalli, Kshithija

AU - Sequist, Lecia V.

AU - Mak, Raymond H.

AU - Benes, Cyril H.

AU - Hong, Theodore S.

AU - Gurtner, Kristin

AU - Krause, Mechthild

AU - Baumann, Michael

AU - Kang, Jing X.

AU - Whetstine, Johnathan R.

AU - Willers, Henning

PY - 2017/4/15

Y1 - 2017/4/15

N2 - Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here, we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA doublestrand breaks and repressed putative negative regulators of stem-like properties, such as CRMP1 and BIM. The MLCCpositive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers, with possible implications for prognostic and therapeutic strategies.

AB - Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here, we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA doublestrand breaks and repressed putative negative regulators of stem-like properties, such as CRMP1 and BIM. The MLCCpositive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers, with possible implications for prognostic and therapeutic strategies.

KW - A549 Cells

KW - Animals

KW - Carcinoma, Non-Small-Cell Lung/genetics

KW - ErbB Receptors/metabolism

KW - Female

KW - Heterografts

KW - Humans

KW - Lung Neoplasms/genetics

KW - Male

KW - Mice

KW - Mice, Nude

KW - Mutation

KW - Neoplastic Stem Cells/metabolism

KW - Osteopontin/biosynthesis

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Radiation Tolerance/genetics

KW - Signal Transduction

UR - http://www.scopus.com/inward/record.url?scp=85018841506&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-0808

DO - 10.1158/0008-5472.CAN-16-0808

M3 - Article

C2 - 28202526

SN - 0008-5472

VL - 77

SP - 2018

EP - 2028

JO - Cancer Research

JF - Cancer Research

IS - 8

ER -

Radiation resistance in KRAS-mutated lung cancer is enabled by stem-like properties mediated by an osteopontin-EGFR pathway

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this