The goal of anti-cancer treatments is to specifically remove tumors without harming healthy cells. Many cancer cells rely on intracellular proteolysis for their growth, resulting in an anticancer approach based on the inhibition of proteolysis and with it a plethora of anticancer agents. This approach has proven to be effective and has been approved by the FDA for the treatment of multiple myeloma and more recently Mantle Cell Lymphoma. Despite this progress, success remains limited. There are indeed mechanisms that allow cancer cells with altered proteolysis to survive. Understanding these mechanisms is essential for the development of complementary therapies that will reduce or even reverse drug resistance and thus broaden the scope of these drugs.

In this work, researchers from our laboratory studied the effect of cullin-RING ubiquitin ligases (CRL) inhibition in prostate cancer cells and identified potential targets and treatments that sensitize these cells this inhibition. The researchers find that inhibition of CRL globally affects cell signaling by stimulating both tumor suppressor and pro-oncogenic processes. The result of anti-CRL therapy depends on the degree of inhibition. Thus, partial inhibition of CRL activates a transcriptional program that blocks the cell cycle and makes cancer cells behave similar to healthy and differentiated prostatic cells. It is of interest to note the potential dangerousness of this dormant state. Indeed, by stopping proliferation, this state ensures the long-term survival of cancer cells with a low level of proteolysis and protects them against various types of damage.
On the other hand, the complete suppression of CRL obtained with a higher concentration of chemical inhibitor kills the cancer cells by causing damage to the DNA. However, those conditions may also be toxic to normal cells, thus compromising the selectivity of treatment.

By carefully analyzing the underlying molecular mechanisms that enable a cancer cell to resist drugs, these results provide new insights into the anti-cancer approach that targets CRLs. The systematic analysis proposed by the authors leads to the design of treatments based on critical doses of drug cocktails that could reliably shift the balance in prostate cancer treatment toward positive patient outcomes.