Predicting chemoresistance in lung adenocarcinoma through the analysis of drug induced signalling dynamics — ASN Events
  1. Schedule
  2. Session 6: Signalling Network in Medicine
  3. Predicting chemoresistance in lung adenocarcinoma through the analysis of drug induced signalling dynamics

Predicting chemoresistance in lung adenocarcinoma through the analysis of drug induced signalling dynamics (#21)

Jordan Hastings 1 , Jeremy Han 1 , Alvaro Gonzalez-Rajal 1 , Neil Watkins 1 2 , David Croucher 1 2 3
  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. St Vincent's Hospital Clinical School, University of New South Wales, , Sydney, NSW, Australia
  3. School of Medicine, University College Dublin, Dublin, Ireland

Protein kinases are the most frequently mutated family of proteins in cancer, and are therefore an attractive option for targeted therapies. While these mutated kinases frequently behave as cancer drive genes, it is becoming increasingly evident that the inherent adaptability and plasticity of the networks surrounding these kinases can facilitate resistance to both targeted therapies and chemotherapy drugs. One example of this is lung adenocarcinoma, which is frequently resistant to frontline platinum-based chemotherapy. Using a genome-wide siRNA screen for synthetic lethality with platinum therapy, we previously identified a number of kinase signalling pathways strongly implicated in this resistance. Based upon these findings we have now profiled the dynamic response of these signalling pathways during treatment with platinum chemotherapy, and assessed the contribution of these dynamics to determining drug sensitivity.

Using a stratified panel of lung adenocarcinoma cell lines, we utilised bead-based multiplexing technology to profile the cisplatin-induced dynamics of the PI3K/mTOR, MAPK, SMAD, STAT and NF-κB pathways, along with key DNA damage response proteins and apoptosis mediators. A principal component analysis of this dataset identified two opposing signalling axes, upon which the stratified cell lines were distributed according to their degree of platinum resistance. In this analysis, the resistant cell lines were placed within a region of elevated PI3K/mTOR signalling, whilst the sensitive cell lines underwent an opposing, late phase double-strand break DNA damage response. Importantly, the inhibition of PI3K/mTOR signalling in these resistant cell lines with the dual inhibitor BEZ235 shifted these cell longs along this signalling axis and promoted an increase in the double-strand break DNA damage response and apoptosis.

Therefore, this study has identified a potential therapeutic strategy for effective combination therapy in chemoresistant lung adenocarcinoma, whilst also demonstrating the utility of in-depth analysis of drug-induced signalling dynamics for identifying causal effectors of drug resistance.