Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer

Antileukemic Activity and Mechanism of Drug Resistance to the Marine Salinispora tropica Proteasome Inhibitor Salinosporamide A (Marizomib)

“…An identical point mutation was recently identified in bortezomib-resistant THP1 cells (Franke et al, 2012), bortezomib-resistant A549 nonsmall-lung cancer cells (de Wilt et al, 2012), and PR-924-resistant 8226/PR8 cells (Niewerth et al, 2014b). The PR-924-resistant cell line 8226/PR8 harboring the M45V mutation showed 4.3-fold cross-resistance to salinosporamide A (data not shown), further confirming the impact of the M45V mutation in conferring salinosporamide A resistance.…”

“…This finding demonstrates that PSMB5 mutations have an evolutionary ancestor in conferring proteasome inhibitor resistance. Point mutations in the PSMB5 gene introducing single amino acid substitutions in the bortezomib-binding pocket of the b 5 subunit were previously found in bortezomib-resistant leukemic cell lines (Lu et al, 2008;Oerlemans et al, 2008;Ri et al, 2010;Franke et al, 2012;Verbrugge et al, 2012), bortezomib-resistant JY lymphoblastoid cells (Verbrugge et al, 2013), and in nonsmall-cell lung cancer cells (de Wilt et al, 2012), all pointing to this subunit as a key determinant in mediating drug resistance to proteasome inhibitors.…”

“…In vitro biochemical experiments, however, revealed that introduction of the A49V point mutation did not recapitulate the full salinosporamide A resistance phenotype as the original SalI subunit (Kale et al, 2011). Since hematologic tumor cell lines with in vitro acquired resistance to bortezomib have also displayed similar mutations in exon 2 of PSMB5 (Oerlemans et al, 2008;Ruckrich et al, 2009;Ri et al, 2010;Balsas et al, 2012;de Wilt et al, 2012;Franke et al, 2012;Verbrugge et al, 2012), this points to a common mechanism of resistance to proteasome inhibitors.…”

Hallmarks of the ageing lung

“…The essential role of the proteasome for cell cycle control makes this a prime target for tumour therapy, as indicated by the rising numbers of proteasome inhibitors in clinical trials including lung cancer [157][158][159]. Elevated levels of proteasomes, therefore, represent an evasive strategy of tumour cells to chemotherapy [160][161][162].…”

Getting to the root of the problem: the causes of relapse in multiple myeloma

“…One compelling possibility is that proteasome inhibition may be averted by mutation of the PI-binding site. Multiple studies of acquired PI resistance in cell lines adapted to PI exposure in vitro have indeed suggested that mutation of the PI-binding site on the proteasome b5 subunit can produce almost complete cellular resistance to PIs [13][14][15][16][17]. Strikingly, however, sequencing studies of primary MM have failed to identify similar proteasome mutations in patients with clinical PI resistance [18][19][20][21], indicating that PIs likely do bind and inhibit the proteasome in PI-refractory MM in patients.…”