Early Research May Support Targeting PGM3 in Lung Cancer With Concurrent Mutations

By: Victoria Kuhr, BA
Posted: Thursday, March 31, 2022

For non–small-cell lung cancer (NSCLC) with concurrent mutations in the oncogene KRAS and the tumor suppressor gene LKB1, most therapies have seemed to be ineffective. In the search for an effective approach to treating this type of lung cancer, Jiyeon Kim, PhD, of the University of Illinois at Chicago, and colleagues propose that genetic or pharmacologic suppression of N-acetylglucosamine-phosphate mutase 3 (PGM3)—an enzyme downstream of GFPT2 (glutamine-fructose-6-phosphate transaminase 2 [GFPT2])—may reduce the growth of such co-mutant tumors. These study findings were published in Cells.

The study focused on certain NSCLC cell lines—A549 [KRAS], H460 [KRAS], H2122 [KRAS], H1373 [KRAS], and Calu-6 [KRAS]—which were obtained from Hamon Cancer Center Collection at The University of Texas Southwestern Medical Center.

To examine the effect of inhibition of PGM3 on tumor growth in vivo, nude mice were subcutaneously injected with an isogenic pair of H1373 with or without LKB1 expression. Mice were treated with the PGM3 inhibitor FR054 at 500 mg/kg twice a day when palpable tumors were detected. KRAS/LKB1 co-mutant cells generated bigger tumors compared with KRAS-mutant cells alone. Notably, FR054 weakened the growth of these co-mutant tumors to a level similar to KRAS-mutant tumors, whereas the same treatment enhanced the growth of KRAS-mutant tumors. Reduced tumor burdens were related to both decreased proliferation and increased programmed cell death.

Finally, high levels of PGM3 mRNA seemed to correlate with poor prognoses in patients with NSCLC, breast cancer, and bladder cancer. This suggests that FR054 treatment may have therapeutic potential for a broader range of tumor types.

Disclosure: The study authors reported no conflicts of interest.

Cells

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