FAM46C is a tumor suppressor protein initially identified in multiple myeloma (MM) and increasingly recognized for its role in other cancers. Despite its importance, research on FAM46C therapeutic potential in combination with targeted treatments remains limited. Sphingosine kinases (SPHK1 and SPHK2) are key regulators of sphingolipid signaling, a crucial pathway for maintaining cell structure and function, which is frequently deregulated in tumors. Recent evidence from our lab suggested that FAM46C expression synergized with treatment with SK1-I, a pan-SphK inhibitor. Here, we concentrated on SPHK1, the sphingosine kinase primarily associated to cancer, and explored the synergistic impact of induced FAM46C expression alongside treatment with PF-543, a specific SPHK1 inhibitor.

We first conducted data mining in the DepMap database to determine a potential correlation between FAM46C expression and sensitivity to PF-543 in multiple myeloma (MM) cell lines. Upon identifying a correlation, we validated our findings in vitro by assessing cells’ sensitivity to PF-543 in presence or absence of functional FAM46C expression. The results we obtained were further validated in an in vivo xenograft model established by injecting NOD scid gamma with OPM2 cells harbouring either wt FAM46C or the loss-of-function D90G variant in presence or absence of PF-543 administration.

We found a correlation between expression of a functional FAM46C and cell sensitivity to PF-543. In vitro, MM cells re-expressing functional FAM46C exhibited greater sensitivity to PF-543 compared to cells expressing the loss-of-function D90G variant. Conversely, down-modulation of FAM46C lead to a reduction of the cytotoxic efficacy of PF-543 in MM cell lines. Using our in vivo xenograft model we found that FAM46C-expressing MM tumors were sensitive to PF-543 while tumors harboring the D90G loss-of-function variant of FAM46C were not. Our results indicate that expression of a functional FAM46C can indeed sensitize cells to PF-543 treatment. Future studies should explore whether wt FAM46C synergizes with other SphK1 inhibitors or combination therapies, as well as the precise molecular mechanisms underlying this effect.

Overall, our findings indicate that FAM46C plays a crucial role in drug response, enhancing sensitivity to PF-543 in both in vitro and in vivo settings. Our results reveal a novel synergistic interaction between FAM46C expression and SPHK1 inhibition, presenting a promising therapeutic approach for MM treatment.