Progress towards understanding resistance to therapy in EGFR mutant lung cancers
UALC-funded researchers have discovered a new way lung cancers become resistant to treatment, providing a new target for therapy. A team led by UALC Medical Committee member and former grantee Dr. William Pao has shown an additional mechanism that leads to resistance to treatment in EGFR-mutated lung cancers: amplification of the gene HER2.
EGFR mutation is one of the more common genetic drivers of lung cancer, occurring in 10-30% of non-small cell lung cancers. Targeted EGFR inhibitors (erlotinib and gefinib) can often lead to dramatic and long-lasting responses, but all tumors eventually become resistant and progress. One such mechanism of resistance is the T790M mutation, a second mutation to EGFR that enables it to become active even in the presence of the inhibitor. Approximately 60% of resistant tumors have this additional mutation to EGFR.
Researchers are currently working on new EGFR inhibitors, to improve upon current drugs and combat resistance. Afatinib (a second generation EGFR inhibitor) is one such drug, and is showing promising results in a Phase III trial for patients with untreated EGFR mutant tumors. To combat resistance, researchers are testing a novel drug combination of afatinib and cetuximab (an EGFR antibody therapy currently approved for colon cancer). This drug combination showed a 40% response rate in a clinical trial among lung cancer patients with acquired resistance to EGFR inhibitors.In 2010, UALC funded Dr. Katerina Politi to investigate how patients with EGFR mutated lung cancers become resistant to this new combination.
Afatanib has some POTENTIAL advantages over erlotinib in that it can block EGFR and another related protein, HER2. The team, including Drs. Mark Kris (UALC Medical Committee), Vincent Miller, Marc Ladanyi and Katerina Politi (UALC grantees) and others, investigated how HER2 can contribute to sensitivity or resistance to this drug combination. The team’s data suggest that HER2 may play an important role in why some patients respond and become resistant to EGFR inhibitors. They found HER2 was amplified in up to 12% of patients with resistance, exclusive of the T790M mutation. If verified in additional testing, it could potentially be the second most common mechanism of resistance to EGFR inhibitors.