Ligand‐triggered resistance to molecular targeted drugs in lung cancer: Roles of hepatocyte growth factor and epidermal growth factor receptor ligands

<jats:p>Recent advances in molecular biology have led to the identification of new molecular targets, such as epidermal growth factor receptor (<jats:italic> <jats:styled-content style="fixed-case">EGFR</jats:styled-content> </jats:italic>) mutations and echinoderm microtubule‐associated protein‐like 4 (<jats:styled-content style="fixed-case">EML</jats:styled-content>4) – anaplastic lymphoma kinase (<jats:styled-content style="fixed-case">ALK</jats:styled-content>) fusion gene, in lung cancer. Dramatic response has been achieved with <jats:styled-content style="fixed-case">EGFR</jats:styled-content> inhibitors (gefitinib and erlotinib) and an <jats:styled-content style="fixed-case">ALK</jats:styled-content> inhibitor (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to molecular targeted drugs include gatekeeper mutations in the target gene and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand‐triggered receptor activation as well. For example, hepatocyte growth factor (<jats:styled-content style="fixed-case">HGF</jats:styled-content>), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream <jats:styled-content style="fixed-case">PI</jats:styled-content>3<jats:styled-content style="fixed-case">K</jats:styled-content>/<jats:styled-content style="fixed-case">A</jats:styled-content>kt pathway and triggers resistance to <jats:styled-content style="fixed-case">EGFR</jats:styled-content> inhibitors in <jats:italic> <jats:styled-content style="fixed-case">EGFR</jats:styled-content> </jats:italic> mutant lung cancer cells. Moreover, <jats:styled-content style="fixed-case">EGFR</jats:styled-content> ligands activate <jats:styled-content style="fixed-case">EGFR</jats:styled-content> and downstream pathways and trigger resistance to crizotinib in <jats:italic> <jats:styled-content style="fixed-case">EML</jats:styled-content>4‐<jats:styled-content style="fixed-case">ALK</jats:styled-content> </jats:italic> lung cancer cells. These observations indicate that signals from oncogenic drivers (<jats:styled-content style="fixed-case">EGFR</jats:styled-content> signaling in <jats:italic> <jats:styled-content style="fixed-case">EGFR</jats:styled-content> </jats:italic>‐mutant lung cancer and <jats:styled-content style="fixed-case">ALK</jats:styled-content> signaling in <jats:italic> <jats:styled-content style="fixed-case">EML</jats:styled-content>4‐<jats:styled-content style="fixed-case">ALK</jats:styled-content> </jats:italic> lung cancer) and ligand‐triggered bypass signals (<jats:styled-content style="fixed-case">HGF</jats:styled-content>‐<jats:styled-content style="fixed-case">M</jats:styled-content>et and <jats:styled-content style="fixed-case">EGFR</jats:styled-content> ligands‐<jats:styled-content style="fixed-case">EGFR</jats:styled-content>, respectively) must be simultaneously blocked to avoid the resistance. This review focuses specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies that are under development for overcoming resistance to molecular targeted drugs in lung cancer. (<jats:italic>Cancer Sci</jats:italic> 2012; 103: 1189–1194)</jats:p>