p53 mutations and loss of p53 function confer multidrug resistance in neuroblastoma

Abstract

These data suggest that some neuroblastomas acquire p53 mutations during therapy, which is associated with a loss of p53 function, and can confer high-level multidrug resistance.

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G1 checkpoint‐defective neuroblastoma

“…Two of them (LAN1 and SKNJC2) totally lost p53 protein expression due to nonsense mutations 17 (our unpublished data), SKNAS expressed a shorter p53 form due to the C-terminus truncation, 18 and BE(2)N showed a strong p53 band reflecting enhanced p53 stability due to a missense mutation at codon 135. 8 Chemoresistance in G 1 checkpoint-defective neuroblastoma cell lines…”

“…4b). Dysfunction in cell cycle checkpoint due to direct p53 mutations has been documented for some time, 8,14 while the effects of MDM2/p14 ARF determined as described in Materials and Methods. Column, mean; bars, SD.…”

“…13 Thus, even if not all MDM2/p14 ARF abnormalities were responsive to Chk1 inhibition as our findings suggested, it is conceivable about one-third of all relapsed neuroblastoma patients could potentially benefit from a combination therapy utilizing Chk1 inhibitor and chemotherapeutic drug. Moreover, since recent studies suggest that most p53 mutations found in neuroblastomas are acquired after chemotherapy, while MDM2/p14 ARF abnormalities and MDM2 polymorphism are found primarily at diagnosis, 8,10,11,13 it seems reasonable to exploit Chk1 inhibitors either early on at diagnosis in patients with documented MDM2/p14 ARF abnormalities, or after recurrence when tumors have acquired p53 mutations. One can extrapolate this strategy even further to prevent the emergence of resistance while patients are undergoing induction therapy.…”

“…6 Dysfunction in p53 pathway is increasingly recognized as one of the key factors that contribute to drug resistance. 7,8 This can be due to either direct p53 mutations or aberrations in its regulatory factors, such as MDM2 amplification and p14 ARF deletion. Mutations in p53 are found in many human cancers.…”

“…The frequency of p53 mutations does increase following intensive chemotherapy and/or at relapse. 8 Alternatively, MDM2 amplification and p14 ARF deletion found in relapsed or prior-treated neuroblastoma could also derail p53 response. MDM2 polymorphism SNP309 was recently shown to influence clinical outcome in metastatic neuroblastomas.…”