Effect of KRAS oncogene substitutions on protein behavior

Implications for signaling and clinical outcome

Nathan T. Ihle, Lauren A. Byers, Edward S. Kim, Pierre Saintigny, J. Jack Lee, George R. Blumenschein, Anne Tsao, Suyu Liu, Jill E. Larsen, Jing Wang, Lixia Diao, Kevin R. Coombes, Lu Chen, Shuxing Zhang, Mena F. Abdelmelek, Ximing Tang, Vassiliki Papadimitrakopoulou, John D. Minna, Scott M. Lippman, Waun K. Hong & 4 others Roy S. Herbst, Ignacio I. Wistuba, John V. Heymach, Garth Powis

Research output: Contribution to journalArticle

224 Citations (Scopus)

Abstract

Background Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. Methods We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided. Results Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P =. 046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. Conclusions Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalJournal of the National Cancer Institute
Volume104
Issue number3
DOIs
StatePublished - Feb 8 2012

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Oncogenes
Mutant Proteins
Non-Small Cell Lung Carcinoma
Proteins
Neoplasms
Survival
Mutation
Disease-Free Survival
Phosphatidylinositol 3-Kinase
MAP Kinase Kinase Kinases
Cell Line
Protein Array Analysis
Extracellular Signal-Regulated MAP Kinases
Amino Acid Substitution
Survival Analysis
Transducers
Mitogens
Transcriptome
Codon
Sarcoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ihle, N. T., Byers, L. A., Kim, E. S., Saintigny, P., Lee, J. J., Blumenschein, G. R., ... Powis, G. (2012). Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome. Journal of the National Cancer Institute, 104(3), 228-239. https://doi.org/10.1093/jnci/djr523

Effect of KRAS oncogene substitutions on protein behavior : Implications for signaling and clinical outcome. / Ihle, Nathan T.; Byers, Lauren A.; Kim, Edward S.; Saintigny, Pierre; Lee, J. Jack; Blumenschein, George R.; Tsao, Anne; Liu, Suyu; Larsen, Jill E.; Wang, Jing; Diao, Lixia; Coombes, Kevin R.; Chen, Lu; Zhang, Shuxing; Abdelmelek, Mena F.; Tang, Ximing; Papadimitrakopoulou, Vassiliki; Minna, John D.; Lippman, Scott M.; Hong, Waun K.; Herbst, Roy S.; Wistuba, Ignacio I.; Heymach, John V.; Powis, Garth.

In: Journal of the National Cancer Institute, Vol. 104, No. 3, 08.02.2012, p. 228-239.

Research output: Contribution to journalArticle

Ihle, NT, Byers, LA, Kim, ES, Saintigny, P, Lee, JJ, Blumenschein, GR, Tsao, A, Liu, S, Larsen, JE, Wang, J, Diao, L, Coombes, KR, Chen, L, Zhang, S, Abdelmelek, MF, Tang, X, Papadimitrakopoulou, V, Minna, JD, Lippman, SM, Hong, WK, Herbst, RS, Wistuba, II, Heymach, JV & Powis, G 2012, 'Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome', Journal of the National Cancer Institute, vol. 104, no. 3, pp. 228-239. https://doi.org/10.1093/jnci/djr523
Ihle, Nathan T. ; Byers, Lauren A. ; Kim, Edward S. ; Saintigny, Pierre ; Lee, J. Jack ; Blumenschein, George R. ; Tsao, Anne ; Liu, Suyu ; Larsen, Jill E. ; Wang, Jing ; Diao, Lixia ; Coombes, Kevin R. ; Chen, Lu ; Zhang, Shuxing ; Abdelmelek, Mena F. ; Tang, Ximing ; Papadimitrakopoulou, Vassiliki ; Minna, John D. ; Lippman, Scott M. ; Hong, Waun K. ; Herbst, Roy S. ; Wistuba, Ignacio I. ; Heymach, John V. ; Powis, Garth. / Effect of KRAS oncogene substitutions on protein behavior : Implications for signaling and clinical outcome. In: Journal of the National Cancer Institute. 2012 ; Vol. 104, No. 3. pp. 228-239.
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abstract = "Background Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. Methods We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided. Results Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P =. 046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. Conclusions Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.",
author = "Ihle, {Nathan T.} and Byers, {Lauren A.} and Kim, {Edward S.} and Pierre Saintigny and Lee, {J. Jack} and Blumenschein, {George R.} and Anne Tsao and Suyu Liu and Larsen, {Jill E.} and Jing Wang and Lixia Diao and Coombes, {Kevin R.} and Lu Chen and Shuxing Zhang and Abdelmelek, {Mena F.} and Ximing Tang and Vassiliki Papadimitrakopoulou and Minna, {John D.} and Lippman, {Scott M.} and Hong, {Waun K.} and Herbst, {Roy S.} and Wistuba, {Ignacio I.} and Heymach, {John V.} and Garth Powis",
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TY - JOUR

T1 - Effect of KRAS oncogene substitutions on protein behavior

T2 - Implications for signaling and clinical outcome

AU - Ihle, Nathan T.

AU - Byers, Lauren A.

AU - Kim, Edward S.

AU - Saintigny, Pierre

AU - Lee, J. Jack

AU - Blumenschein, George R.

AU - Tsao, Anne

AU - Liu, Suyu

AU - Larsen, Jill E.

AU - Wang, Jing

AU - Diao, Lixia

AU - Coombes, Kevin R.

AU - Chen, Lu

AU - Zhang, Shuxing

AU - Abdelmelek, Mena F.

AU - Tang, Ximing

AU - Papadimitrakopoulou, Vassiliki

AU - Minna, John D.

AU - Lippman, Scott M.

AU - Hong, Waun K.

AU - Herbst, Roy S.

AU - Wistuba, Ignacio I.

AU - Heymach, John V.

AU - Powis, Garth

PY - 2012/2/8

Y1 - 2012/2/8

N2 - Background Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. Methods We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided. Results Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P =. 046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. Conclusions Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.

AB - Background Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. Methods We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided. Results Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P =. 046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. Conclusions Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.

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