GCs are a major component of successful ALL therapies, and leukemia cell resistance to GCs (assessed either in vitro or in vivo) confers a poor prognosis. As steroid hormones, GCs bind to the GCR (encoded by the nuclear receptor subfamily 3 gene [NR3C1]), and this leads to translocation of the receptor into the nucleus, where it acts as a transcription factor and binds to GC response elements triggering the activation or repression of gene transcription, which ultimately results in diminished proliferative capacity and apoptosis of ALL cells.

GC therapy can be associated with severe ADRs with sometimes debilitating consequences. For example, adolescent females are at highest risk for an epiphyseal arteriopathy leading to avascular osteo necrosis (AVN), which often necessitates early joint replacement. Although several PGx investigations were designed to identify predictors of AVN, besides sex and age, no clinically actionable predictors have been identified to date. Unlike the situation in TP myelotoxicity where TPMT and NUDT15 have been proven as clinically actionable common genetic variants with large effect sizes, GC-induced AVN might be mediated by numerous rarer variants with small effect sizes, necessitating more complex models.

In parallel to the situation in ADRs, GC resistance of leukemia cells has also been identified to be rather polygenic in nature. In integrated genomic and epigenomic investigations in primary ALL cells and in vitro model systems, dysregulation of key components (i.e., caspase 1 encoded by CASP1, and its activator NLR family pyrin domain containing 3 encoded by NLRP3) of the so-called NALP3 inflammasome pathway—which cleaves and inactivates the GCR NR3C1—were identified as a novel GC resistance mechanism.[1] Reduced somatic promotor methylation in CASP1 and NLRP2 was found in ALL cells resistant to GCs, leading to an increase of transcription and translation of CASP1 and NLRP3, resulting in higher mRNA and protein levels of CASP1 and NLRP3 and enhanced caspase1 cleavage and inactivation of the GCR.[1] This discovery opens several avenues for further action (e.g., prospectively screen childhood ALL samples for CASP1 and NLRP3 expression to alter treatment in patients whose leukemia cells carry these variants and to search for small molecule inhibitors of CASP1), although there are no known caspase1 inhibitors approved for clinical use (e.g., VX-765 or VRT 0431198 are preclinical candidates).

Moreover, in a GWAS on diagnostic and relapsed ALL samples, variants in NR3C1/NR3C2 (encoding the GCRs), in CREBBP (encoding the histone lysine acetyltransferase CREB binding protein), and in NSD2 (encoding the nuclear receptor binding SET domain protein 2) were found to be significantly enriched or exclusively present in relapse; variants in these genes have been identified previously to be implicated in GC resistance.[2] Monitoring for these and other drug resistance/relapse-associated mutations (e.g., variants in NT5C2, PRPS1, or MSH2) may help to early identify emergence of a TP- or GC-resistant ALL cell clone; such patients may then benefit from the introduction of other therapies, such as the proteasome inhibitor bortezomib or, if the ALL is of B-cell origin, from CD19-targeting immunotherapies such as chimeric antigen receptor (CAR) T cells or a bispecific antibody therapy with blinatumumab, or CD22-targeting therapy with inotuzumab ozogamicin (InO).

More recently, it was discovered that approximately 50% of GC-resistant ALL have low expression of the G protein–coupled receptor CELSR2. Downregulation of CELSR2 was associated with reduced expression of the GCR and with increased expression of the antiapoptotic protein BCL2 after GC treatment, and preclinical studies showed that the BCL2 inhibitor venetoclax can mitigate this form of GC resistance in ALL.[3]

References

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[1] Paugh SW, Bonten EJ, Savic D, et al. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat Genet. 2015;47(6):607–614.

[2] Li B, Brady SW, Ma X, et al. Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. Blood. 2020;135(1):41–55.

[3] Autry RJ, Paugh SW, Carter R, et al. Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia. Nat Cancer. 2020;1:329–344.

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