Do we know how Velcade doesn't work?

In my recent piece on the proteasome inhibitor Argyrin A, a commenter (okay, so far THE commenter) noted something I can't argue with, that there is not a well nailed-down understanding of why proteasome inhibition is lethal to tumor cells. I probably should write up a further exploration of how they might work, but I really need to skim the literature for any new findings (so far, nothing stunning).

As Yogi Berra might say, Velcade (bortezomib) is effective in cancer except when it isn't. Indeed, in cell lines in culture the stuff is devastating, but that certainly isn't what's seen in the clinic. In that setting, there is this obnoxious tease of a signal in Phase I (remember, in oncology Phase I is tried in patients with the disease, not with healthy volunteers as in most indications) followed by cruel let-down in Phase II. Even in diseases where the drug works, such as myeloma, it doesn't work in all patients and some patients become resistant. Perhaps that resistance is the key to the puzzle: understand how tumors stop being sensitive and you'd understand the ones which are never sensitive to start with.

Three recent papers (in Blood, J Pharmacol Exp Ther & Exp Hematol) have found the same mechanism for this transition. Alas, none are free & I've only read the abstract (one of many reasons to swing by the MIT library soon All point to overexpression and/or mutation in PSMB5, the proteasome subunit which binds Velcade. Two of the papers report different point mutations, but both in the Velcade binding pocket and in at least one a reduced affinity for Velcade was demonstrated. Game, set & match?

Well, perhaps not. First of all, all three studies are in cell lines, two in closely related ones. As noted above, cell lines are highly imperfect for exploring proteasome inhibition in particular (and not uniformly reliable for oncotherapeutic pharmacology in general). Judging from the abstracts, none of them went fishing around in patient samples, or if they did they came up dry. Given that PSMB5 is an obvious candidate gene for bortezomib resistance, I'm pretty sure this one's been hammered on hard by my former colleagues. Nobody likes to publish the Journal of Negative Results, which I'm pretty sure is where it would end up. Almost certainly some patients will be found who went from sensitivity to resistance due to mutations in PSMB5, but at the moment it's not the long-awaited (and much desired/needed) central hypothesis of why proteasome inhibition works and which patients it should be used in.