1) MLN4924, acting alone, inactivates CRLs by inhibiting cullin neddylation to cause the accumulation of multiple tumor-suppressive substrates, leading to blockage of tumor angiogenesis and inflammatory responses, induction of senescence or apoptosis in cancer cells, and protective autophagy which serves as an overall survival signal to cancer cells. 2) MLN4924, in combination with chemoradiation, sensitizes resistant cancer cells to conventional therapies.