MAPK- and AKT-activated thyroid cancers are sensitive to group I PAK inhibition
Abstract
The mortality rate from thyroid cancer has been rising, and patients who do not respond to standard treatments have few therapeutic options. This underscores the urgent need for novel therapies targeting aggressive forms of the disease. In such cases, oncogenic activation of the MAPK pathway—via BRAF and RAS mutations or gene rearrangements—and activation of the PI3K pathway—through PIK3CA mutations or PTEN loss—are well-documented. In previous work, we identified elevated expression and activity of p21-activated kinases (PAKs) at the invasive fronts of aggressive human thyroid tumors and showed that PAK1 plays a key role in regulating thyroid cancer cell migration. We also demonstrated BRAF-dependent, MEK-independent crosstalk between the MAPK and PAK pathways, suggesting that dual inhibition of PAK and MEK may produce synergistic effects.
In this study, we explored this therapeutic strategy. Using two group I PAK inhibitors, G-5555 and FRAX1036, we observed that pharmacologic inhibition reduced thyroid cancer cell viability, impeded cell cycle progression, and suppressed cell migration and invasion, with G-5555 showing greater potency. Notably, combining G-5555 with vemurafenib yielded synergistic effects in BRAFV600E-mutant thyroid cancer cell lines. Furthermore, G-5555 significantly reduced thyroid tumor size by over 50% (P < 0.0001) and decreased carcinoma incidence (P = 0.0167) in a BRAFV600E-driven mouse model of papillary thyroid cancer, despite persistent MAPK pathway activity. These findings support group I PAKs as promising therapeutic targets in thyroid cancer and highlight their functional role in BRAFV600E-driven tumor progression.