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. and Powis, Garth (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. doi:10.1093/jnci/djr523

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Author 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
Title Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome
Journal name Journal of the National Cancer Institute   Check publisher's open access policy
ISSN 0027-8874
Publication date 2012-02
Sub-type Article (original research)
DOI 10.1093/jnci/djr523
Open Access Status
Volume 104
Issue 3
Start page 228
End page 239
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted 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.
Keyword Lung-Cancer
Ras Mutations
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 118 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 131 times in Scopus Article | Citations
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Created: Fri, 04 Oct 2013, 13:46:12 EST by Jill Larsen on behalf of School of Medicine