Abstract
IntroductionGrowing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.Materials and MethodsWe investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients’ outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh–Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).ResultsAmong the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients’ biopsies. Shh was significantly (p < 0.05) enriched in youth (age < 68), male, nonsmokers, patients with a PS > 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.ConclusionThese data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.
Highlights
Growing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFRmutated (EGFRm) non-small cell lung cancer (NSCLC)
The introduction of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) as first-line therapy for the treatment of EGFR-mutated Non-small cell lung cancer (NSCLC) patients has led to longer progression-free survival (PFS) and higher response rates compared to platinum-based chemotherapy [3,4,5,6]
Forty-seven (62.2%) NSCLC were Exon 19 mutated, 22 (29.7%) were L858R mutated patients, and 5 cases were found with another EGFR mutation type (Table 1)
Summary
Growing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFRmutated (EGFRm) non-small cell lung cancer (NSCLC). The introduction of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) as first-line therapy for the treatment of EGFR-mutated NSCLC patients has led to longer progression-free survival (PFS) and higher response rates compared to platinum-based chemotherapy [3,4,5,6]. Studies have addressed many sources of EGFR-TKI resistance, underlining the involvement of EGFR-dependent (i.e., T790M or C797S resistance mutations) or EGFR-independent molecular aberrations (i.e., MET amplification or the activation of other oncogenic pathways) [9]. The expression/ activation levels of these pathways have been proposed as predictive biomarker for EGFR-TKI therapy
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