Targeted drugs, such as sorafenib, olaparib and bevacizumab, are a class of drugs that selectively act on specific tumor cell targets, thereby killing or inhibiting proliferation of tumor cells. Targeted therapies are an integral part of current cancer treatment, and despite their success, treatment-induced drug resistance remains a major cause of poor prognosis [118]. Some studies on FAO and resistance to targeted therapy have been reported recently (Fig. 2C), Table 2 and Fig. 4A summarized the roles and mechanisms of FAO in targeted therapy resistance.Fig. 4: FAO in targeted therapy resistance and endocrinotherapy resistance.A Role and mechanism of FAO in targeted therapy resistance, B role and mechanism of FAO in endocrinotherapy resistance. Created with BioRender.com.Full size imageTable 2 Roles and mechanisms of FAO in targeted therapy resistance.Full size tableAn association between lncRNAs and cancer resistance has been demonstrated [119, 120]. A recent study found that the expression of lnc01056 is closely related to the prognosis of patients with HCC [121]. Loss of lnc01056 activates PPARα-mediated FAO, leading to resistance of HCC cells to sorafenib [122]. Tumor-initiating stem-like cells (TICs) are present in a variety of tumors, including HCC, and are involved in cancer drug resistance [123, 124]. A study found that the homeobox transcription factor NANOG inhibited mitochondrial OXPHOS and activated FAO through the TLR4/E2F1/NANOG pathway, promoting resistance of HCC TIC to sorafenib [125]. Another study reported that FAO enhancement led to cancer cell resistance to bevacizumab. A recent study identified extracellular matrix (ECM) deposition and enhanced FAO in CRC cells from patients resistant to bevacizumab. Deposition of ECM activates lipolysis in hepatic stellate cells by activating the focal adhesion kinase/yes-associated protein pathway, thereby enhancing FAO in CRC cells and leading to their resistance to bevacizumab [126]. In addition, tissue hypoxia induced by bevacizumab treatment promotes AMPK phosphorylation and enhances FAO, leading to CRC cell resistance to bevacizumab [127]. Several MAPK pathway inhibitors have been approved by the US Food and Drug Administration (FDA) for the treatment of clinical melanoma, including BRAF and MEK kinase inhibitors, which are poorly tolerated and are prone to development of resistance during treatment [128]. When melanoma cells are treated with the BRAF inhibitor vemurafenib for a long time, FAO is up-regulated, which contributes to the resistance of melanoma cells to vemurafenib [129]. In addition, a study found that peroxisomal FAO (pFAO) in BRAF-mutated melanoma persister cells was up-regulated through the PPARα-PGC1α-ACOX1 axis, and the use of pFAO inhibitors combined with BRAF/MEK inhibitors to treat melanoma delayed the emergence of resistance to targeted therapy [130]. The researchers also found that PPARα was up-regulated and FAO was enhanced in BRAF-mutated melanoma cells after MAPK inhibition therapy, leading to cancer cell resistance [131]. In addition to melanoma, a recent study reported that FAO enhancement can lead to targeted therapy resistance in LC. KRAS mutant NSCLC is highly susceptible to resistance to the MEK inhibitor trametinib. It has been reported that FAO is significantly enhanced in trametinib-resistant tumor cells, coordinately driving the OXPHOS system to meet the energy needs of tumor cells while protecting them from apoptosis. Targeting FAO can increase the sensitivity of drug-resistant tumor cells to trametinib [26]. Minimal residual disease (MRD) is closely related to cancer drug resistance [132, 133]. It has been found that advanced HGSOC MRD cells are characterized by adipocyte-like gene expression, and rely on FAO to survive and develop resistance to olapani. However, the specific mechanism leading to up-regulation of FAO is still unclear [134]. Venetoclax combined with azacytidine (ven/aza) is a very effective treatment for AML, but drug resistance is still widespread. It has been shown that resistance of AML stem cells to ven / aza occurs through the up-regulation of FAO, which occurs by a mechanism related to mutations in the RAS pathway genes [135]. Notably, the PI3K/AKT/mTOR pathway is closely related to the mitochondrial FAO [36, 136], and, more importantly, it is involved in the regulatory process of Venetoclax resistance in AML cells [137, 138]. However, the role played by the PI3K/AKT/mTOR pathway in the process of tumor drug resistance due to FAO dysregulation is still unclear. Ibrutinib is one of the main drugs used in the treatment of CLL, but drug resistance is still a problem [139, 140]. A study identified metabolic reprogramming in ibrutinib-resistant cells, which was characterized by abnormal activation of FAO. Inhibition of FAO resensitized drug-resistant cells to ibrutinib [141].Lei, Y., Cai, S., Zhang, JK. et al. The role and mechanism of fatty acid oxidation in cancer drug resistance.
Cell Death Discov. 11, 277 (2025). https://doi.org/10.1038/s41420-025-02554-1https://doi.org/10.1038/s41420-025-02554-1 bu içeriği en az 2500 kelime olacak şekilde ve alt başlıklar ve madde içermiyecek şekilde ünlü bir science magazine için İngilizce olarak yeniden yaz. Teknik açıklamalar içersin ve viral olacak şekilde İngilizce yaz. Haber dışında başka bir şey içermesin. Haber içerisinde en az 14 paragraf ve her bir paragrafta da en az 80 kelime olsun. Cevapta sadece haber olsun. Ayrıca haberi yazdıktan sonra içerikten yararlanarak aşağıdaki başlıkların bilgisi var ise haberin altında doldur. Eğer bilgi yoksa ilgili kısmı yazma.:
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Article References:Lei, Y., Cai, S., Zhang, JK. et al. The role and mechanism of fatty acid oxidation in cancer drug resistance.
Cell Death Discov. 11, 277 (2025). https://doi.org/10.1038/s41420-025-02554-1
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02554-1
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Tags: cancer prognosis and treatment outcomesendocrinotherapy resistance mechanismsfatty acid oxidation in cancer treatmentmechanisms of drug resistance in cancermetabolic pathways in cancer therapyovercoming cancer drug resistancePPARα and fatty acid metabolismrole of lncRNAs in cancersorafenib and hepatic cancer resistancetargeted drug therapies and efficacytargeted therapy drug resistancetumor-initiating cells in cancers
