Abstract
Lung cancers globally account for 12% of new cancer cases, 85% of these being Non Small Cell Lung Cancer (NSCLC). Therapies like erlotinib target the key player EGFR, which is mutated in about 10% of lung adenocarcinoma. However, drug insensitivity and resistance caused by second mutations in the EGFR or aberrant bypass signaling have evolved as a major challenge in controlling these tumors. Recently, AMPK activation was proposed to sensitize NSCLC cells against erlotinib treatment. However, the underlying mechanism is largely unknown. In this work we aim to unravel the interplay between 20 proteins that were previously associated with EGFR signaling and erlotinib drug sensitivity. The inferred network shows a high level of agreement with protein-protein interactions reported in STRING and HIPPIE databases. It is further experimentally validated with protein measurements. Moreover, predictions derived from our network model fairly agree with somatic mutations and gene expression data from primary lung adenocarcinoma. Altogether our results support the role of AMPK in EGFR signaling and drug sensitivity.
Highlights
Lung cancer is the second most prevalent cancer in both men and women and accounts for 12% of all new cases of cancers reported worldwide[1]
TKI response in patient-derived lung cancer xenografts, or mutations have been observed in these models[14]: In more detail, the proteins coding for mTOR, PRKAA1, RAF1, RPS6KA1, and RPS6KAB1 were differentially expressed in Reverse Phase Protein Arrays (RPPA) analysis of Non Small Cell Lung Cancer (NSCLC) xenograft models[14]
Targeted therapy of EGFR is well established for lung ADC, but frequently fails due to acquired drug resistances
Summary
Lung cancer is the second most prevalent cancer in both men and women and accounts for 12% of all new cases of cancers reported worldwide[1]. In consequence several monoclonal antibodies against EGFR have been developed These include gefitinib (Iressa) and erlotinib (Tarceva). A T790M mutation occurs in more than 50% of EGFR-mutant lung cancers[11] To overcome such treatment failures new targeted therapies need to be developed, possibly within a combinatorial or poly-pharmacological approach[12,13]. A recent study has shown that activation of AMPK sensitizes EGFR wildtype H1299 cells and xenografts to erlotinib treatment[14]. This synergistic effect was less obvious in EGFR mutated tumor models that may be due to endogenous AMPK activity and solely EGFR TKI (Tyrosine Kinase Inhibitor) sensitivity. BCL1 EGFR ESPL1 GSK3B PIK3C3 PRKAA1 PRKAB1 RAF1 RPS6KA1 RPS6KB1 SRC STK11 TSC1 TSC2 MTOR TRUB2 ITGB4 GSK3A LEPR WDR3
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