The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells

Background: PTC596 is a novel small molecule that inhibits microtubule polymerization, and its clinical development is being pursued for the treatment of various solid cancers. In this study, we explored the preclinical efficacy of PTC596, both as a monotherapy and in combination with proteasome inhibitors, in treating multiple myeloma (MM).

Methods: We evaluated the effects of PTC596 on MM cell lines and primary MM samples in vitro, as well as in vivo using MM cell line xenografts. We investigated the potential synergy of PTC596 with proteasome inhibitors bortezomib and carfilzomib, assessing their combined effects on MM cell proliferation and growth.

Results: PTC596 effectively inhibited the proliferation of MM cell lines and primary MM samples both in vitro and in vivo. The combination of PTC596 with bortezomib or carfilzomib showed synergistic effects, significantly inhibiting MM cell growth in vitro. In a xenograft model using immunodeficient mice, the combination of PTC596 with bortezomib demonstrated a synergistic effect on MM cell line growth, with acceptable tolerability. Mechanistically, PTC596 induced cell cycle arrest at the G2/M phase, leading to apoptotic cell death, which was linked to its inhibition of microtubule polymerization. RNA sequencing analysis revealed that PTC596 and its combination with bortezomib altered cell cycle progression and apoptosis pathways in MM cells. Notably, the combination therapy enhanced the endoplasmic reticulum stress induced by bortezomib, providing further insight into the underlying mechanism of action.

Conclusion: Our findings suggest that PTC596, either alone or in combination with proteasome inhibitors, may offer promising therapeutic strategies to improve outcomes for patients with multiple myeloma.