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Professor Yadollah Omidi has a Ph.D. degree in Pharmaceutical Sciences (2003, Cardiff University, UK) and completed a postdoctoral program (2004) at Cardiff University. He is currently working as a full professor at Nova Southeastern University College of Pharmacy, Florida. Prof. Omidi’s research in advanced targeted diagnosis and therapy of diseases have resulted in over 300 published papers in international journals, 27 book chapters, and a few patents. His H-index is 61 and i10-index is 238. He has consecutively been listed among top 1% highly cited scientists worldwide by WoS-ESI.

Epidermal growth factor receptors (EGFRs) overexpressed by various solid tumors are involved in the initiation, progression, and metastasis of different malignancies such as breast cancer and colorectal cancer (CRC).^1,2 EGFRs are considered clinically valid oncomarkers which can be targeted to inhibit/eradicate cancer cells using various advanced treatment modalities such as monoclonal antibodies (mAbs), Ab-armed nanomedicines, Ab-drug nanoconjugates, hybrid Ab scaffolds like bispecific constructs, aptamer-decorated nanosystems, gene therapy, and so forth.^1-7 Specific binding of epidermal growth factors (EGF) to EGFRs results in their dimerization and activation of downstream signaling mechanisms such as MAPK/ERK, PI3K/AKT/mTOR pathways leading to the regulation of cancer cell proliferation, invasion, and angiogenesis.^8,9 Anti-EGFR mAbs such as cetuximab (CET) were shown to substantially improve the overall survival of metastatic CRC (mCRC) patients with wild-type KRAS genotypes.¹⁰ However, in mCRC patients, the therapeutic response to anti-EGFR therapy can be limited due to the development of multiple resistance mechanisms.¹¹ Numerous genetic factors contribute to the development of resistance mechanisms in cancer cells against anti-EGFR mAbs. These factors include:

• EGFR gene copy number: The number of copies of the EGFR gene can influence the response to anti-EGFR mAbs.

• Protein expression of EGFR ligands: The levels of ligands that bind to EGFR, such as EGF and TGF-alpha, can impact the efficacy of anti-EGFR mAbs.

• HER2 and MET gene amplification: Amplification of HER2 and MET genes, which are involved in signaling pathways related to EGFR, can contribute to resistance against anti-EGFR mAbs.

• Activation of EGFR downstream cascade signaling pathways: Mutations or alterations in downstream signaling pathways of EGFR, such as KRAS, NRAS, BRAF, and PIK3CA, can lead to resistance against anti-EGFR mAbs.

• Loss of PTEN and STAT3 phosphorylation: Inactivation of the tumor suppressor PTEN and abnormal phosphorylation of STAT3 might be associated with resistance to anti-EGFR mAbs.

• Epithelial-mesenchymal transition (EMT) occurrence: EMT, a process where epithelial cells acquire mesenchymal characteristics, seems to be linked to resistance against anti-EGFR mAbs in cancer cells.

These factors appear to contribute collectively to the emergence of resistance mechanisms in cancer cells, reducing the effectiveness of anti-EGFR mAbs.^12,13 Besides, the role of non-genetic factors is a highly debated issue even though little is known about the exact resistance mechanism of such a phenomenon. All in all, it is necessary to explore new strategies for improving the cytotoxic impacts of anti-EGFR mAbs, enhancing apoptosis in CRC, and overcoming drug resistance mechanisms in mCRC patients.¹⁴

In recent studies, the crucial functions of small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs) have gained significant attention, particularly in relation to tumor progression and the development of resistance mechanisms against anti-EGFR mAbs in CRC.¹⁵ Of these, lncRNA biomacromolecules are considered complex ncRNAs structures, which have been indiscriminately described as RNA molecules longer than 200 nucleotides with no translation into proteins.¹⁶ These biomacromolecules appear to modulate CRC via altering the expression of genes, triggering chromosomal remodeling, orchestrating transcriptional/post-transcriptional impacts, and self-translation of lncRNAs into polypeptides.^17,18 Additionally, lncRNAs can prevent therapeutic-induced cell death, stimulate the EMT phenomenon, and promote non-cell-autonomous resistance mechanisms.¹⁹ Table 1 lists some of the aberrant expressions of specific lncRNAs together with their potential biological and clinical relevance during colorectal carcinogenesis.^20,21

Remarkably, lncRNAs are believed to be potential modulators of genes related to the cancer cells resistance mechanisms, which might (i) influence intracellular drug concentrations, (ii) prompt alternative signaling pathways, and (iii) modify drug efficacy by hindering cell cycle regulation and DNA damage response. All in all, they are probably responsible for developing resistance to anticancer agents, especially anti-EGFR mAbs.³¹ LncRNAs may induce CET-resistance in mCRC through different mechanisms, including (i) the EGFR mutations and disrupting the CET binding to EGFR (lncRNA POU5F1P4),³⁷ (ii) the mutations of the EGFR downstream pathways (lncRNA CRART16),³⁸ (iii) the activation of Wnt/β-catenin signaling (lncRNA MIR100HG),²⁶ and (iv) the activation of the parallel pathway such as MET (lncRNA UCA1).³⁹ Remarkably, lncRNA CRART16 was reported to elicit CET-resistance in CRC cells most likely by functioning as a miR-371a-5p sponge and thereby enhancing the expression of erythroblasts Leukemia viral oncogene Homolog 3 (ERBB3) through the miR-371a-5p/ERBB3/MAPK pathway.³⁸ The downregulation of lncRNAs LNC00973 seems to improve CET resistance in mCRC cells most likely by regulating the metabolism of glucose.²⁹ Besides, lncRNA HCG18 appears to facilitate the progress of the CRC resulting in CET-resistance through upregulation of PD-L1 and also suppressed CD8+ T lymphocytes cells via sponging miR-20b-5p.²⁸ The upregulation of exosomal lncRNA UCA1,²⁹ and downregulation of lncRNA POU5F1P4 were shown to be involved with the emergence of drug resistance in CET-sensitive CRC cells.³⁷ Recent studies have supported lncRNAs' roles in anti-EGFR drug-resistance inducing based on lncRNAs-mRNAs, or lncRNAs-miRNAs-mRNAs regulatory networks through the EGFR, RAS, and PI3K/AKT signaling pathways.⁴⁰ Fig. 1 illustrates the possible involvement of lncRNAs on EGFR-related signaling pathways.

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Fig. 1.

Schematic representation of the upregulation impacts of certain lncRNAs on the EGFR-related signaling pathways. Epidermal growth factor receptor (EGFR), as a cell surface receptor, regulates cell growth, proliferation, and survival. Dysregulation of EGFR signaling is commonly observed in cancer, leading to uncontrolled cell growth and tumor progression. A complex network of genes and miRNAs can be modulated, including those associated with the RAS/RAF/MEK/ERK pathways. LncRNA CRART16 upregulates ERBB3 expression through miR-371a-5p, lncRNA NEAT1 downregulates miR-193a-3p, and lncRNA H19 attenuates miR-193b-mediated inhibition. These functions activate the EGFR/RAS/RAF/MAPK pathways and contribute to anti-EGFR resistance in CRC.

Fig. 1.

Schematic representation of the upregulation impacts of certain lncRNAs on the EGFR-related signaling pathways. Epidermal growth factor receptor (EGFR), as a cell surface receptor, regulates cell growth, proliferation, and survival. Dysregulation of EGFR signaling is commonly observed in cancer, leading to uncontrolled cell growth and tumor progression. A complex network of genes and miRNAs can be modulated, including those associated with the RAS/RAF/MEK/ERK pathways. LncRNA CRART16 upregulates ERBB3 expression through miR-371a-5p, lncRNA NEAT1 downregulates miR-193a-3p, and lncRNA H19 attenuates miR-193b-mediated inhibition. These functions activate the EGFR/RAS/RAF/MAPK pathways and contribute to anti-EGFR resistance in CRC.

Collectively, the mechanisms underlying the CRC resistance to anti-EGFR therapy are the most complicated issue, and the lncRNAs spectrum associated with this resistance mechanism remained largely unknown due to the paucity of lncRNAs-specific microarray/RNA sequencing analysis. Upon some published data, lncRNAs can affect the therapeutic efficacy of anti-EGFR mAbs mainly through intracellular signaling even though their specific mechanisms are yet to be fully addressed. Notably, the interaction between ncRNAs and their crosstalk with anti-EGFR resistance-related pathways needs to be fully understood. To specifically target and inhibit the overexpressed lncRNAs, various therapeutic approaches can be developed. First, antisense oligonucleotides (ASOs), antagomirs, small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), miRNA sponges, and CRISPR/Cas9-based genome editing technique, which can be used to directly interfere with the expression or function of the overexpressed lncRNAs, leading to their inhibition or degradation. Second, treatment strategies that involve the use of tumor suppressor lncRNAs. Some lncRNAs have the ability to suppress tumor growth and progression. By introducing or enhancing the expression of tumor suppressor lncRNAs, it may be possible to regulate the functional expression of oncomiRs and restore normal cellular functions. Third, small molecule inhibitors, which specifically target the functional domains or binding sites of overexpressed lncRNAs, can be developed. Fourth, screening natural compounds and extracts for their ability to inhibit overexpressed lncRNAs can be another approach. Finally, nanoscale formulations such as Ab-drug nanoconjugates can be employed. These involve coupling therapeutic agents, such as small molecule drugs or antibodies, to nanoparticles with potential to specifically target and suppress the cells or tissues expressing the lncRNAs. Altogether, therapeutic strategies for targeting overexpressed lncRNAs include the use of antisense oligonucleotides, RNA interference, genome editing, exploitation of tumor suppressor lncRNAs, and nanoscale treatment modalities like Ab-drug nanoconjugates. These approaches hold promise in combating cancers associated with aberrant lncRNA expression. Despite the recent progress in ncRNA-based therapeutics, understanding the precise role of lncRNAs and related molecular mechanisms in anti-EGFR therapy and CET resistance in mCRC requires deep insights. In this regard, mismatched base pairing to non-target mRNAs, unexpected effects on normal tissue, and especially off-target effects are still tremendous challenges that need to be addressed. Thus, further evaluations are required to improve therapeutics' specificity, delivery, and tolerability using lncRNAs. Moreover, lncRNAs can be applied in monitoring and forecasting treatment response and resistance to personalized treatments to improve clinical outcomes.

Competing interests

None to be stated.

Ethical statement

The present study was approved by the Ethics Committee of Tabriz University of Medical Sciences (Ethical No. IR.TBZMED.REC.1401.338).

Funding sources

The support provided by the Liver and Gastrointestinal Diseases Research Center at Tabriz University of Medical Sciences (grant #69709) to MAK is acknowledged.

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