Pathway Interplay: Activation of EGFR, ERK, and AKT in Early-Stage Lung Adenocarcinomas
Alexandra E Kovach, Vicente Morales-Oyarvide, Daniel E Shvetz, Swathi Tammireddy, Veronica Klepeis, Eugene J Mark, Dora Dias Santagata, A John Iafrate, Mari Mino-Kenudson. Massachusetts General Hospital (MGH), Boston, MA; MGH, Boston, MA
Background: Lung adenocarcinomas have several driver mutations including EGFR and KRAS mutations that share downstream signaling for tumor initiation and maintenance. The activation/phosphorylation of signaling pathways relative to driver mutations has not been well studied in clinical samples. We investigated the phosphorylation states of EGFR, ERK (a target of KRAS in the MAPK pathway), and AKT (PI3K pathway) in molecularly defined early-stage lung adenocarcinomas and evaluated their interaction with each other, with driver mutations, and with clinicopathologic characteristics.
Design: The cohort consisted of 155 resected Stage 0-2 lung adenocarcinomas previously analyzed for EGFR, KRAS, and other driver mutations by a multiplex PCR-based assay. Tumors were stained on tissue microarrays with antibodies against phospho (p)-EGFR, p-ERK, and p-AKT. Average composite scores were assigned using H-scores (0-300). Cut-offs for positivity were based on mean scores and expression in normal epithelium. Clinicopathologic parameters included smoking status, tumor size, predominant histological pattern, and recurrence-free survival (RFS).
Results: p-EGFR expression was associated with p-AKT expression (p<0.001) but not with p-ERK expression. p-ERK expression was associated with KRAS mutations (p<0.0001) but not with EGFR or other mutations. Neither p-EGFR nor p-AKT expression was associated with any mutation including EGFR. Similarly, p-ERK expression was more prevalent in tumors from smokers (p=0.020) and those with in situ carcinoma or minimal invasion (p=0.023). Interestingly, the 3-year RFS was significantly better in subjects with p-EGFR expression than those without (p=0.037), and p-ERK expression was associated with improved 3-year RFS across the entire cohort (82.6% vs. 65.4%, p=0.025) and in cases with extensive invasion (75.4%vs. 65.4%, p=0.086). Other clinicopathologic correlations were not found.
Conclusions: These results confirm that KRAS mutations correlate with activation of the downstream target ERK, especially in early stage tumors and that ERK inhibition may be in turn an effective therapeutic strategy for KRAS mutants. Factors in addition to EGFR mutations may activate EGFR, which is more likely to activate PI3K-AKT than MAPK/ERK, at least on the protein level. Whether p-EGFR and/or p-ERK expression predict improved survival after resection of early stage lung adenocarcinomas needs to be evaluated in larger studies.
Monday, March 4, 2013 1:00 PM
Poster Session II # 285, Monday Afternoon