Here we show for the first time that HAS2 driven HA synthesis and signaling through RHAMM is a major driver of growth in NSCLC cells that have lost AGL expression and provide preclinical evidence that personalized inhibition of the HAS2-HA-RHAMM axis may benefit patients with low tumor AGL and high HAS2 or RHAMM expression. Here, HMMR is linked to non-small cell lung carcinoma.