Unravelling the suboptimal response of <i><scp>TP</scp>53</i>‐mutated chronic lymphocytic leukaemia to ibrutinib

Guarini, Anna; Peragine, Nadia; Messina, Monica; Marinelli, M; Ilari, Caterina; Cafforio, Luciana; Raponi, Sara; Bonina, Silvia; Mariglia, Paola; Mauro, Francesca Romana; Gaïdano, Gianluca; Giudice, Ilaria Del; Foà, Robin

doi:10.1111/bjh.15613

Cited by 8 publications

(8 citation statements)

References 15 publications

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“…TP53 defect, with its associated predisposition to genomic instability and clonal complexity [ 42 , 43 , 44 ], likely facilities the development of resistance mechanisms such as BTK or PLCγ2 mutations in the case of ibrutinib [ 45 , 46 ]; and BCL-2 mutation, Mcl-1 upregulation, or metabolic reprogramming in the case of venetoclax [ 47 , 48 ]. Gene-expression profiling has also suggested a reduced dependence on BCR signaling in TP53 -mutated CLL [ 49 ]. Moreover, patients under ibrutinib or venetoclax therapy continue to be at risk of Richter transformation, with TP53 disruption and DNA damage response (DDR) alterations featuring prominently in this process [ 50 , 51 , 52 ].…”

Section: P53 Pathway Defects As Adverse Prognostic Biomarkers In Cllmentioning

confidence: 99%

Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

Kwok

Agathanggelou

Davies

et al. 2021

Cancers

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The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the ‘undruggable’ p53 pathway therefore arguably represents the holy grail of cancer research. In recent years, several strategies have been proposed to exploit p53 pathway defects for cancer treatment. Such strategies include upregulating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations. In this review, we will examine the biological and clinical implications of p53 pathway defects, as well as our progress towards development of therapeutic approaches targeting the p53 pathway, specifically within the context of CLL. We will appraise the opportunities and pitfalls associated with these therapeutic strategies, and evaluate their place amongst the array of new biological therapies for CLL.

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Section: P53 Pathway Defects As Adverse Prognostic Biomarkers In Cllmentioning

confidence: 99%

Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

Kwok

Agathanggelou

Davies

et al. 2021

Cancers

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“…Additionally, CLL patients that progress or develop Richter’s transformation on ibrutinib recurrently harbor mutations of tumor-suppressor TP53, splicing factor SF3B1, or NFκB pathway regulator CARD11, however, whether these genetic aberrations may directly impact response to ibrutinib during Richter’s transformation remains unclear ( 80 ). Though, despite good initial response in most of CLL patients, it has been shown that mutations in TP53 are responsible for a worse prognosis in a long-term ibrutinib treatment and they also partially protect CLL cells in vitro from ibrutinib-induced apoptosis and inhibition of proliferation ( 104 – 107 ). This might be related to the recently described role of p53 in the negative regulation of BCR signalling ( 31 , 32 ).…”

Section: Genetic Mechanisms Of Ibrutinib Resistancementioning

confidence: 99%

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Ondrisova

Mráz

2020

Front. Oncol.

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The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström’s macroglobulinemia (WM). However, these “BCR inhibitors” function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11 , CCND1 , BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

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“…12,13 This can be due to an intrinsic genomic instability and a greater possibility of acquiring additional mutations conferring drug resistance and more frequent relapses in the longterm. 7 Moreover, in vitro apoptosis and inhibition of proliferation are inferior in TP53 mutated than in WT cells exposed to ibrutinib, pointing to different mechanisms of cell fitness control in addition to the BCR pathway, 15 that can make the difference over time.…”

mentioning

confidence: 99%