–Various molecular mechanisms of resistance to PI3K inhibitors have been described preclinically and clinically.
In an unbiased exploratory analysis of samples from patients treated with copanlisib, a 16-gene mutation signature that separated responders from nonresponders was identified, the authors said.
The finding suggests that genetic aberrations dictate response to PI3K inhibitors, they noted.
“This 16-gene signature included TNFAIP3, CREBBP, and PRDM1, which are known to be important in the molecular pathogenesis of DLBCL,” they wrote. A composite score was developed to reflect the numerical presence or absence of mutations in the gene set, they explained, adding that patients with a high composite score had a significantly higher overall response rate and longer progression-free survival than did patients with a lower score.
In addition, idelalisib treatment resulted in a feedback activation of PI3Ka in ABC DLBCL cells.
“This rebound of PI3K activity was overcome by subsequent PI3Ka inhibition in preclinical DLBCL models, further underscoring the necessity of inhibiting both PI3Ka and PI3Kd to achieve responses in ABC DLBCL,” they wrote, adding that “[i]n ABC DLBCL models treated with the PI3Ka/PI3Kd inhibitor AZD8835, activated CARD11 mutations were identified as a mechanism of resistance.”
Investigations looking at various treatment combinations to overcome resistance to PI3K inhibition and improve the efficacy of targeted approaches are under way, they said.
For example, copanlisib plus the BCL-2 inhibitor venetoclax showed “synergistic activity in BCR-dependent DLBCLs, with genetic bases for BCL-2 dysregulation in vitro and in vivo,” and combination treatment with umbralisib and the proteasome inhibitor carfilzomib showed synergistic cytotoxicity in B-cell lymphoma, they said, noting that the latter combination is currently being evaluated in patients with DLBCL.
This work was supported by a research grant from the Deutsche Krebshilfe. Dr. Xu reported having no financial disclosures.
