P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse

Abstract

Key Points• The increased expression of PI3K p110a in mantle cell lymphoma, particularly at relapse, suggests a role for p110a in disease progression.• A high PIK3CA/PIK3CD ratio identifies patients unlikely to respond to p110d inhibitors and supports use of dual p110a/p110d inhibitors in MCL.Phosphoinositide-3 kinase (PI3K) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis, but early-phase studies of the PI3K p110d inhibitor GS-1101 have reported inferior responses in MCL compared with other non-Hodgkin lymphomas.Because the relative importance of the class IA PI3K isoforms p110a, p110b, and p110d in MCL is not clear, we studied expression of these isoforms and assessed their contribution to PI3K signaling in this disease. We found that although p110d was highly expressed in MCL, p110a showed wide variation and expression increased significantly with relapse. Loss of phosphatase and tensin homolog expression was found in 16% (22/138) of cases, whereas PIK3CA and PIK3R1 mutations were absent. Although p110d inhibition was sufficient to block B-cell receptor-mediated PI3K activation, combined p110a and p110d inhibition was necessary to abolish constitutive PI3K activation. In addition, GDC-0941, a predominantly p110a/d inhibitor, was significantly more active compared with GS-1101 against MCL cell lines and primary samples. We found that a high PIK3CA/PIK3CD ratio identified a subset of primary MCLs resistant to GS-1101 and this ratio increased significantly with relapse. These findings support the use of dual p110a/p110d inhibitors in MCL and suggest a role for p110a in disease progression. (Blood. 2013;121(12):2274-2284 IntroductionMantle cell lymphoma (MCL) is an aggressive disease in the vast majority of patients and is incurable with conventional therapy. Although there has been an improvement in median overall survival (OS), from the 2-to 4-year range cited in earlier series to between 5 and 7 years more recently, 1 outcome is still one of the poorest among B-cell lymphomas. MCL is characterized by t(11;14), which results in juxtaposition of the IgH enhancer on chromosome 14 to the cyclin D1 locus on chromosome 11, leading to the characteristic overexpression of cyclin D1. Secondary hits primarily leading to defective DNA damage repair and cell -cycle dysregulation occur in MCL, 2 and a number of studies have implicated activation of the phosphoinositide-3 kinase (PI3K) pathway, one of the most commonly dysregulated pathways in human cancer, in the pathogenesis of this disease.3-5 The serine-threonine kinase AKT, which is the major downstream target of PI3K, is thought to be important in MCL survival through its role in stabilizing cyclin D1 messenger RNA (mRNA), preventing nuclear export of cyclin D1 by phosphorylation of GSK-3b and increasing cyclin D1 translation through mammalian target of the rapamycin (mTOR) activation. [6][7][8] PI3Ks are heterodimeric lipid kinases that have a regulatory and a catalytic subunit. Class IA PI3Ks primarily signal downstream of the B-cell recept...

The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells

“…In this sense, it has been reported that expression of p110 isoform can maintain constitutive PI3K signaling despite p110 inhibition. 36 The inhibition of PI3K by NVP-BKM120 results in dephosphorylation of Akt and subsequent regulation of a number of proteins including FoxO3a. The tumor suppressor genes of the FoxO subfamily of Forkhead transcription factors that includes FoxO3a (or FKHRL1), FoxO1a (or FKHR), and FoxO4a (or AFX) are critical effectors downstream of Akt.…”

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

“…Objective response rates were seen in about 50% of the patients with relapsed or refractory B-cell malignancies (41,42). Although GS-1101 shows great potential as a candidate therapy for CLL and NHL, some recent studies with experimental models have suggested that pan-class I PI3K inhibition could offer broader activity in a variety of hematologic malignancies (43)(44)(45). Such observations should be treated with caution: although GS-1101 demonstrated moderate activity during preclinical development, it has shown impressive activity in the clinical setting, which has been attributed to its action on the tumor microenvironment, as opposed to its activity within leukemia and lymphoma cells themselves (46).…”

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

“…Analysis of MCL cell lines and primary samples suggest that PIK3CA amplification may be a mechanism of resistance to p110d inhibition. 35 Hodgkin's lymphoma PI3K is constitutively activated in Hodgkin's and ReedSternberg (HRS) cells and is associated with prolonged cell survival. 62 In Hodgkin's lymphoma (HL) cell lines, PI3Kd was detected at higher levels than other class I PI3K isoforms.…”

“…While PI3Kd was the most consistently expressed, PI3Kα expression was significantly greater in patients with MCL who had relapsed multiple times and PIK3CA amplification was associated with resistance to p110d inhibition. 35 Several ongoing trials are evaluating GDC-0941, including a phase I dose-escalation study in patients with NHL or solid tumors (clinicaltrials.gov identifier:00876122). Preliminary results in patients with solid tumors have been reported.…”