Prognostic and Predictive Value of KRAS Mutation in NSCLC

With great interest, we have read the article by Zer et al.1Zer A. Ding K. Lee S.M. et al.Pooled analysis of the prognostic and predictive value of KRAS mutation status and mutation subtype in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors.J Thorac Oncol. 2016; 11: 312-323Abstract Full Text Full Text PDF Scopus (47) Google Scholar regarding the prognostic effect of KRAS mutation in NSCLC. They conducted a pooled analysis to investigate the role of KRAS mutation subtypes in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). Overall, KRAS mutation was not associated with prognostic and predictive benefit; however, these types of KRAS mutation were associated with different prognostic outcomes. In the placebo arms, patients with G12C/V mutations showed a favorable prognosis compared with those with G12D/S or G12A/R mutations (with median overall survival values: 6.3, 1.8, and 3.9 months, respectively; p = 0.01). When compared with the placebo group, EGFR TKIs significantly improved survival only in patients with G12D/S mutations (hazard ratio = 0.49, 95% confidence interval: 0.24–1.00, p = 0.05). Although these differences may be caused by activation of different downstream pathways (e.g., Akt and MEK),2Ihle N.T. Byers L.A. Kim E.S. et al.Effect of KRAS Oncogene substitutions on protein behavior: implications for signaling and clinical outcome.J Natl Cancer Inst. 2012; 104: 228-239Crossref PubMed Scopus (357) Google Scholar we suggest another biological pathway that is associated with EGFR/KRAS signaling. Liver kinase B1 gene (LKB1), a serine/threonine kinase, is a frequently mutated tumor suppressor gene in NSCLC. It regulates multiple cellular functions, such as cell bioenergetics metabolism, cell cycle arrest, and apoptosis. Despite significant association with KRAS mutation,3Ding L. Getz G. Wheeler D.A. et al.Somatic mutations affect key pathways in lung adenocarcinoma.Nature. 2008; 455: 1069-1075Crossref PubMed Scopus (2169) Google Scholar the relationship between liver kinase B1 (LKB1) and KRAS subtype has not been well understood. Nevertheless, LKB1-deficient KRAS-mutant (G12D) tumor shows a more invasive and metastatic phenotype with poorer prognosis than KRAS mutation alone in a mouse model of KRAS-induced NSCLC.4Ji H. Ramsey M.R. Hayes D.N. et al.LKB1 modulates lung cancer differentiation and metastasis.Nature. 2007; 448: 807-810Crossref PubMed Scopus (793) Google Scholar This finding suggests that patients with G12D/S may have poor prognosis owing to concurrent LKB1 mutation. Moreover, the presence of concurrent LKB1 mutations may also account for treatment efficacy of EGFR TKIs. LKB1 deficiency leads to enhanced mitochondrial metabolism that is associated with activation of adenosine monophosphoate–activated protein kinase and suppression of mammalian target of rapamycin signaling, resulting in increased sensitivity to EGFR TKI treatment without mutationally activated EGFR.5Whang Y.M. Park S.I. Trenary I.A. et al.LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small cell lung cancer (NSCLC) cells.Oncogene. 2016; 35: 856-866Crossref Scopus (40) Google Scholar The authors showed that LKB1-mutant EGFR wild-type (WT) cell lines are more sensitive to erlotinib than are LKB1/EGFR WT cell lines. Overexpression of LKB1 into LKB1-null A549 cells results in increased basal phosphorylation of adenosine monophosphoate–activated protein kinase subunit α and causes resistance to erlotinib. Furthermore, stable silencing of LKB1 in LKB1 WT cells increased sensitivity to erlotinib and resulted in less colony formation compared with the vector control. This suggests that LKB1 status may serve as a predictive marker for patients with KRAS mutation when they are treated with EGFR TKIs. The prognostic value of KRAS mutation has been discussed in many trials for decades, yet its value remains unclear. Further understanding of the correlation between KRAS subtype and LKB1 mutation might be helpful in selecting patients who may benefit from EGFR TKIs. The presence of KRAS mutation in colorectal cancer is indicative of nonsensitivity to anti-EGFR antibody therapy; therefore, its use is now part of routine oncology practice. Even so, the determination of KRAS status in the management of NSCLC and other malignancies is not considered standard practice on account of the lack of any convincing evidence that it is a predictive or prognostic marker. Although its role in clinical oncology has not been defined, preclinical and clinical findings suggest that activated mitochondrial signaling induced by LKB1 mutation warrants further investigation in future studies. Pooled Analysis of the Prognostic and Predictive Value of KRAS Mutation Status and Mutation Subtype in Patients with Non–Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase InhibitorsJournal of Thoracic OncologyVol. 11Issue 3PreviewThis pooled analysis of four trials of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) versus placebo was conducted to clarify the prognostic and predictive roles of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (MUTs) and to explore the importance of MUT subtype. Full-Text PDF Open ArchiveResponse to Yamamoto et al.Journal of Thoracic OncologyVol. 11Issue 10PreviewWe thank Yamamoto et al.1 for their comments on our study.2 In their letter they suggest that co-mutations of liver kinase B1 gene (LKB1) and KRAS G12D may account for the differential prognostic and predictive effect we have reported for KRAS transition mutations G12D/G12S and the potential benefit from EGFR tyrosine kinase inhibitors in this subtype. Full-Text PDF Open Archive