Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia

Murali, Ishwarya; Kasar, Siddha; Naeem, Aishath S.; Tyekucheva, Svitlana; Khalsa, Jasneet Kaur; Thrash, Emily M.; Itchaki, Gilad; Livitz, Dimitri; Leshchiner, Ignaty; Dong, Shuai; Fernandes, Stacey M.; Getz, Gad; Johnson, Amy J.; Brown, Jennifer R.

doi:10.1182/blood.2020006765

Cited by 40 publications

(31 citation statements)

References 37 publications

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“…Most of the patients included in this study had never received treatment for CLL (10/13 patients; ‘CLL’ patients listed in Table 2 ). To investigate whether treatment status affected sensitivity to MEK/Bcl‐2 inhibition, we performed the same analysis on a cohort of CLL patients that were treated with the PI3K inhibitor idelalisib as first line or following chemoimmunotherapy (‘JB’ patients listed in Table 2 ) [ 8 ]. Drug sensitivity screens were performed on the patients’ CLL cells collected prior to start of treatment with idelalisib ( n = 6), while the patients were responding to idelalisib ( n = 7), and when the patients had developed resistance to idelalisib ( n = 4) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Such mutations are therefore unlikely to fully explain the sensitivity to MEK inhibition observed here. Furthermore, it has been shown that activation of ERK is associated with resistance to idelalisib in CLL irrespective of mutations in the MAPK pathway [ 8 ]. To investigate underlying mechanisms of the disease‐specific drug sensitivities observed here, we performed high‐throughput profiling of 31 intracellular proteins, including members of the MAPK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…While most studies are on solid tumors, a few ongoing trials study the MEKi binimetinib (NCT02089230), selumetinib (NCT00588809), and trametinib (NCT02016729, NCT00920140, NCT01428427, NCT01476137) in leukemia (Table 1 ). A recent study showed that chronic lymphocytic leukemia (CLL) patients resistant to the phosphatidylinositol‐3 kinase (PI3K) inhibitor idelalisib had activating mutations in MAPK pathway genes, providing a rationale for combined PI3K/MEK inhibition in this group of CLL patients [ 8 ]. Dual targeting of these pathways is currently studied in clinical trials on multiple myeloma (MM; NCT01476137, NCT01989598).…”

Section: Introductionmentioning

confidence: 99%

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Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

et al. 2021

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Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen-activated protein kinase kinase (MEK) inhibitors and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy-chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib-resistant patients remained sensitive to the treatment. This suggests that combined MEK/ Bcl-2 inhibition may be an option for high-risk CLL. To test whether sensitivity could be detected in other B-cell malignancies, we performed drug testing on cell line models of CLL (n = 4), multiple myeloma (MM; n = 8), and mantle cell lymphoma (MCL; n = 7). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease-specific drug sensitivities, we performed flow cytometry-based high-throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) or B-cell lymphoma-extra large (Bcl-xL) predicted low sensitivity to trametinib + venetoclax. The low

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

et al. 2021

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“…In CLL, primary GoF, driver mutations are found in components of not only the NF-κB but also of the RAS-MAPK pathway, as depicted in Figure 3 ( 112 , 113 , 120 ). The very recent report demonstrating that resistance mutations to inhibitors of p110δ selectively affects the MAPK pathway in CLL patients is highly interesting ( 121 ). It shows that also this arm of the BCR pathway can be affected by resistance mutations ( Figure 1 ), although they never appear after BTKi treatment.…”

Section: Recurrent Primary Mutations In B Cell Malignancies Responding To Btkimentioning

confidence: 99%

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Smith

Burger

2021

Front. Immunol.

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Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in the BTK gene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somatic BTK driver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase Cγ2 (PLCγ2). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-κB arm, whereas an inhibitor of the p110δ subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLCγ2 resistance mutations highlight BTK’s non-redundant role in BCR-mediated NF-κB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLCγ2. This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.

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“…Regarding the new targeted therapies (Table 1), mutations in the MAPK pathway are mediators of primary resistance to PI3K inhibitors [61]. Furthermore, activation of ERK1/2 has been associated with ibrutinib resistance [102], raising the possibility that patients with mutations in this pathway might have reduced sensitivity to ibrutinib.…”

Section: Recurrent Mutations and Alterations In Mapk Pathwaymentioning

confidence: 99%

Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets

López‐Oreja

Playà-Albinyana

Arenas

et al. 2021

Cancers

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Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses.

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Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia

Cited by 40 publications

References 37 publications

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets

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