Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review

Singh, Priyanka; Kumar, Veerandra; Gupta, Sonu Kumar; Kumari, Gudia; Verma, Malkhey

doi:10.1007/s12032-021-01462-5

Cited by 38 publications

(35 citation statements)

References 122 publications

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“…The recognition of the PI3K/AKT/mTOR pathway as an important drug target in oncology led to the approval of PI3K inhibitors (as Idelalisib) and mTOR inhibitors (as an example of Sirolimus) for different neoplasias [ 266 ]. In preclinical studies, Everolimus, an mTOR inhibitor, show promising results overcoming TKI resistance in cell lines and ex vivo samples [ 267 , 268 ].…”

Section: Therapeutic Approaches Against Resistancementioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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Section: Therapeutic Approaches Against Resistancementioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

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“…Among these drugs are trabectedin and its analogs [41,42], Mithramycin [43,44], and YK-4-279 and derivatives [45,46]. Although these drugs have reached clinical testing, the results obtained have been, at the moment, discouraging because of the elevated toxicity in some cases [47] and for the intrinsic difficulty in targeting transcription factors with pharmacological approaches [48], not to mention that pharmacological inhibition of EWSR1-FLI1 could require the administration of a drug for prolonged periods to achieve a durable response, as occurs in the case of tyrosine kinase inhibitors (for example, imatibib) [49]. This could lead to a decrease in the drug's efficacy or the appearance of resistance in the clinical setting [50].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma

Cervera

Rodríguez-Martín

Fernández-Tabanera

et al. 2021

Cancers

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Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1–FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1–FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1–FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1–FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1–FLI1 at the cell level should be considered a therapeutic approach to develop in the future.

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“…Several ongoing clinical trials and preclinical studies (257-29) (Table 2) are currently investigating the role of different molecules in IPF pathogenesis to define their anti-proliferative and anti-fibrotic roles (Table 1) which might have good prospects even against lung cancer; these are the anti-IL-13 antibodies (QAX576 and Lebrikizumab), the anti-CCL2 antibodies (Carlumab and CNTO-888), the anti-TGF-β1 antibodies (Fresolimumab and GC1008), the anti-integrin αvβ6 antibodies (BG0011 and STX-100),and the integrin αvβ6 antagonist drugs (GSK3008348), etc. [251][252][253]. Another drug that is actually used and considered feasible in IPF and lung cancer-IPF patients is vantictumab, which influences Wnt signaling and is in Phase I clinical trials for the role of inhibitor of lung fibrosis [254,255] Indeed, a preclinical study demonstrated the anti-fibrotic effects of CG-745, a histone deacetylase (HDAC) inhibitor, in bleomycin mouse models.…”

Section: Therapeutic Agents For Ipf and Lcmentioning

confidence: 99%

Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development

Samarelli

Masciale

Aramini

et al. 2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2–4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine–kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.

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Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review

Cited by 38 publications

References 122 publications

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma

Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development

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