<jats:p>Identifying a common oncogenesis pathway among tumors with different oncogenic mutations is critical for developing anti-cancer strategies. Here, we performed transcriptome analyses on two different models of <jats:italic>Drosophila</jats:italic> malignant tumors caused by Ras activation with cell polarity defects (Ras<jats:sup>V12</jats:sup><jats:italic>/scrib</jats:italic><jats:sup>-/-</jats:sup>) or by microRNA bantam overexpression with endocytic defects (bantam<jats:italic>/rab5</jats:italic><jats:sup>-/-</jats:sup>), followed by an RNAi screen for genes commonly essential for tumor growth and malignancy. We identified that Juvenile hormone Inducible-21 (JhI-21), a <jats:italic>Drosophila</jats:italic> homolog of the L-amino acid transporter 1 (LAT1), is upregulated in these malignant tumors with different oncogenic mutations and knocking down of JhI-21 strongly blocked their growth and invasion. JhI-21 expression was induced by simultaneous activation of c-Jun N-terminal kinase (JNK) and Yorkie (Yki) in these tumors and thereby contributed to tumor growth and progression by activating the mTOR-S6 pathway. Pharmacological inhibition of LAT1 activity in <jats:italic>Drosophila</jats:italic> larvae significantly suppressed growth of Ras<jats:sup>V12</jats:sup><jats:italic>/scrib</jats:italic><jats:sup>-/-</jats:sup> tumors. Intriguingly, LAT1 inhibitory drugs did not suppress growth of bantam<jats:italic>/rab5</jats:italic><jats:sup>-/-</jats:sup> tumors and overexpression of bantam rendered Ras<jats:sup>V12</jats:sup><jats:italic>/scrib</jats:italic><jats:sup>-/-</jats:sup> tumors unresponsive to LAT1 inhibitors. Further analyses with RNA sequencing of bantam-expressing clones followed by an RNAi screen suggested that bantam induces drug resistance against LAT1 inhibitors via downregulation of the TMEM135-like gene <jats:italic>CG31157</jats:italic>. Our observations unveil an evolutionarily conserved role of LAT1 induction in driving <jats:italic>Drosophila</jats:italic> tumor malignancy and provide a powerful genetic model for studying cancer progression and drug resistance.</jats:p>