Researchers from The Weizmann Institute of Science in Rehovot, Israel, identified a new treatment that can prevent lung cancer cells from developing resistance to chemotherapy in mice. The study entitled “Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer” was published in Science Signaling.
High mortality as a consequence of lung cancer is in part due to tumor recurrence that often occurs after a supposedly successful therapy, mainly chemotherapy and other drugs that initially made the tumor go into remission.
Lung cancer patients with primary epidermal growth factor receptor (EGFR) mutations frequently acquire resistance due to a second-site mutation (T790M) regardless of initial positive responses to targeted kinase inhibitors. Unfortunately, data derived from clinical trials showed no survival benefits in patients treated with a monoclonal antibody (mAb) targeting EGFR that inhibited the activation of the mutated receptor, and therefore should overcome resistance to molecules that target its catalytic or ATP-binding site.
Based on some intriguing findings from clinical trials, a question was raised by Prof. Yarden and his student Maicol Mancini: how do the cancer cells manage to overcome the inhibition induced by an anti-EGFR antibody?
The investigators sought to discover what was happening in tumor cells when they were treated with an EGF receptor-blocking antibody.
Using a triple mAb blocking combination the team developed a new strategy to fight tumor recurrence as a consequence of chemotherapy resistance. “The blocked receptor has ‘siblings’ – other receptors that can step up to do the job,” said Prof. Yarden in a news release.
The researchers discovered that the constant blocking of the main EGFR receptor triggered a network of “sibling” receptors: the extracellular signal–regulated kinase (ERK) pathway; the transcription of HER2 (human epidermal growth factor receptor 2) and HER3, which encode other members of the EGFR family; and the gene encoding hepatocyte growth factor (HGF), the ligand for the receptor tyrosine kinase MET, often found in metastatic tumors. The main receptor EGFR antibody drug did not block these extra sibling receptors and therefore allowed tumor cells to re-appear.
The rationale of the study was to generate novel monoclonal antibodies to simultaneously target all three receptors – HER2, HER3, and the original EGFR – to overcome chemotherapy resistance developed by tumor cells. In fact, in isolated cancer cells, the combination treatment inhibited the necessary receptor activation network that enables cancer recurrence.
“Treatment by blocking a single target can cause a feedback loop that ultimately leads to a resurgence of the cancer,” said Prof. Yarden.
Although there is still a long way to go before this triple-treatment approach is translated into the clinic, Prof. Yarden is optimistic that these findings will not only improve the therapeutic protocol for lung cancer but also increase the knowledge of the mechanisms behind cancer drug resistance.
