Herein, we developed the first multiplexed mouse model to study the impact of TBX2 subfamily loss, alongside associated signaling genes (<i>Egr1</i>, <i>Chd2</i>, <i>Tnfaip3a</i>, and <i>Atf3</i>) in <i>Ras</i>-driven lung cancer. Here, ATF3 is linked to lung cancer.