Targeted therapies in lung cancer, novel EGFR inhibitors, mechanisms of drug resistance
Laboratory-based investigations of Targeted Therapies in Lung Cancer Our laboratory work focuses on studying preclinical models of lung cancers that harbor oncogenic alterations. The main focus of our work is to understand how oncogenic alterations found in lung cancer lead to sensitivity of targeted therapies. Furthermore, we extensively study both model systems and patient derived tumors to uncover mechanisms of drug resistance. Through these studies we have been able to identify novel therapeutic strategies for patients with different genomic subtypes of lung cancer.
Preclinical and clinical development of novel EGFR directed therapies The most common mechanism (found in 60% of patients) of resistance to EGFR inhibitors is the secondary EGFR T790M mutation. The initial studies identified a second class of EGFR inhibitors, covalent or irreversible inhibitors, which could still be effective in model systems harboring EGFR T790M. We have extensively studied one such covalent inhibitor, dactominib, both in preclinical models and in lung cancer patients and despite its efficacy in preclinical models, this drug was not clinically effective in EGFR mutant lung cancer patients that had failed first generation inhibitors. One reason for this disconnect pre-clinically and clinically is that the concentrations of dacomitinib required to inhibit EGFR T790M cannot be reached in patients due to the development of on-target dose limiting toxicity (skin rash, mediated by inhibition of wild type (WT) EGFR) at much lower doses. Prompted by these clinical observations, we began working together with Dr. Nathanael Gray (who is a kinase chemist at DFCI) to tackle this problem. These studies led us to identify a previously unknown class of covalent inhibitors, irreversible pyrimidine inhibitors, which were effective EGFR inhibitors This novel chemical class of agents is both more potent than irreversible quinazolines (like dacomitinib) against EGFR T790M and is EGFR wild type sparing thus potentially improving the therapeutic window. At least 7 pharmaceutical companies have now developed clinical agents inspired by our original finding. We led the phase I clinical trial of one of these agents, osimertinib (AZD9291), which was approved by the FDA in November 2015. We continue to study this class of inhibitors and to use both laboratory and clinical studies to develop novel combination therapies.
Clinical trials of targeted therapies in lung cancer Dr. Jänne has led multiple clinical trials of targeted therapies for patients with specific genomic subtypes of lung cancer. Many of these studies have led to either changing or improving the standard of care for patients with lung cancer. Currently, Dr. Jänne is focusing on developing combination targeted therapies and on clinical studies focusing on preventing and/delaying the emergence of drug resistance.