PI3K-AKT-mTOR pathway alterations in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus everolimus combination therapy

Abstract

Background: Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance.Methods: A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor.Results: Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/ uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6).Conclusions: Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.

Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers

“…Clinically actionable PIK3CA mutations in exons 9 and 20 have been previously found in the EGFR-mutant tumours of patients with acquired resistance to firstand second-generation EGFR-TKIs 5,[28][29][30] and could have been selected as a result of TKI selective pressure. In fact, PIK3CA gene alterations have been consistently one of the most frequently co-occurring known TKIresistance alterations in T790M-positive advanced NSCLC 2,31,32 . However, in vitro evidence that these mutations confer resistance to osimertinib is limited.…”

Identification of MX2 as a Novel Prognostic Biomarker for Sunitinib Resistance in Clear Cell Renal Cell Carcinoma

“…To understand the mechanism of how MX2 links to sunitinib resistance, expression of PTEN/Akt signaling was detected by WB, and it turned out that MX2 level was inversely correlated with the PTEN level while consistent with the p-Akt level in cells. Many previous studies have reported that the PTEN/PI3 k/Akt signaling was involved in EGFR-TKI resistance in the non-small cell lung cancer (NSCLC) (Fang et al, 2012;Pérez-Ramírez et al, 2015;Wang et al, 2018;Choi et al, 2019). This signaling was also found as the driver of drug resistance in breast cancer (Araki and Miyoshi, 2018) and hepatocellular carcinoma (Akula et al, 2013).…”

Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review

“…These signalling aberrations emerge in post-treatment tumour biopsies and are attributed to resistance to all TKI generations via activation of mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK), and Akt/mTOR pathways. Within the Akt/mTOR pathway, mutations have been demonstrated in patient-derived tumours within PIK3CA, PTEN, and AKT1 that lead to increased Akt phosphorylation, mTOR-mediated survival signalling, and early disease progression [ 162 , 163 , 164 , 165 ]. Treatment with the mTOR inhibitor everolimus achieved a disappointing PFS of 2.1 months, indicating the requirement for targeted therapies in emergent resistance [ 165 ].…”

“…Within the Akt/mTOR pathway, mutations have been demonstrated in patient-derived tumours within PIK3CA, PTEN, and AKT1 that lead to increased Akt phosphorylation, mTOR-mediated survival signalling, and early disease progression [ 162 , 163 , 164 , 165 ]. Treatment with the mTOR inhibitor everolimus achieved a disappointing PFS of 2.1 months, indicating the requirement for targeted therapies in emergent resistance [ 165 ]. However, strategies are complicated by concurrent EGFR mutations, downstream mutations, and cross-activation from PIK3CA to MEK pathways [ 165 , 206 ].…”

“…Treatment with the mTOR inhibitor everolimus achieved a disappointing PFS of 2.1 months, indicating the requirement for targeted therapies in emergent resistance [ 165 ]. However, strategies are complicated by concurrent EGFR mutations, downstream mutations, and cross-activation from PIK3CA to MEK pathways [ 165 , 206 ]. Within the MEK/ERK proliferation pathway, BRAF and KRAS mutations contribute to resistance.…”