Treatment resistance remains a key clinical challenge for patients with oncogene-driven non-small cell lung cancer (NSCLC). NSCLC is commonly driven by activating mutations in the genes Epidermal Growth Factor Receptor (EGFR) and Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS). EGFR- and KRAS-targeted therapies attack these specific features in cancer cells to block their growth. Unfortunately, cancer cells are not completely killed by these therapies due to these drugs having a cytostatic effect, which facilitates cells regrowing when therapy is stopped and the ability to develop resistance mechanisms over time.
Cancer cells inherently possess an innate imbalance in redox signalling which enables them to tolerate increased cellular stress. Our preliminary studies demonstrate that EGFR- and KRAS-targeted therapies further induce oxidative stress and activate a cascade of cell survival responses in tumour cells, leading to enlarged cell morphology and reduced proliferation. Promising studies from our laboratory demonstrate that combining oncogene-targeted therapy with a pro-oxidant therapy (Dimethylaminoparthenolide, DMAPT) results in a more sustained anti-tumour response and overcomes resistance development. Using the NCI-H1975 tumor xenograft model, EGFR-targeted therapy (Osimertinib) was combined with DMAPT, and 6/7 mice in the combination treatment group had no detectable tumour at day 300 of the study, compared to only 1/8 mice receiving only Osimertinib. DMAPT had minimal activity as a single agent in vivo. These studies demonstrated mice had an overall survival benefit both on, and following combination treatment. Complementary in vitro studies suggest that the combination therapy further exacerbates cellular stress signalling and enhances the anti-tumour effect by overwhelming the tumour cells’ ability to respond to oxidative stress, turning Osimertinib from a cytostatic therapy to cytotoxic in Osimertinib-resistant NSCLC cell lines. Moreover, the ability of DMAPT to promote increased cell death was also observed in combination with KRAS inhibitor Adagrasib in KRAS-mutant NSCLC cell lines.
Manipulating the cellular mechanisms that control how tumour cells respond to oxidative stress represents a novel strategy for promoting a better response to targeted therapy and warrants further exploration.