An empirical review on the resistance mechanisms of epidermal growth factor receptor inhibitors and predictive molecular biomarkers in colorectal cancer

Bhattacharya, Subhamoy

doi:10.1016/j.critrevonc.2023.103916

Cited by 8 publications

(4 citation statements)

References 104 publications

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“…EGFR‐targeted monoclonal antibodies, such as cetuximab, are used to treat KRAS‐wild type metastatic colorectal cancer, but eventually, resistance to this therapy emerges (Bhattacharya, 2023 ; Sforza et al., 2016 ). Since sEVs from CRC cells have previously been reported to induce cetuximab resistance (Yang et al., 2018 ; Zhang et al., 2017 ), we set out to test whether HCT116 sEVs, and in particular Rab11a‐exosomes, might mediate such effects.…”

Section: Resultsmentioning

confidence: 99%

Stress‐induced Rab11a‐exosomes induce amphiregulin‐mediated cetuximab resistance in colorectal cancer

Mason,

Marks,

Fan

et al. 2024

J of Extracellular Vesicle

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Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G‐protein Rab11a. These vesicles, termed Rab11a‐exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a‐exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non‐genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG‐carrying Rab11a‐exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a‐exosomes from cetuximab‐resistant KRAS‐mutant HCT116 cells, can suppress the effects of cetuximab on KRAS‐wild type Caco‐2 CRC cells. Using neutralising anti‐AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a‐exosomes affects its ability to compete with cetuximab. We propose that this Rab11a‐exosome‐mediated mechanism contributes to the establishment of resistance in cetuximab‐sensitive cells and may explain why in cetuximab‐resistant tumours only some cells carry mutant KRAS.

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Section: Resultsmentioning

confidence: 99%

Stress‐induced Rab11a‐exosomes induce amphiregulin‐mediated cetuximab resistance in colorectal cancer

Mason,

Marks,

Fan

et al. 2024

J of Extracellular Vesicle

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show abstract

“…EGFR-targeted monoclonal antibodies, such as cetuximab, are used to treat KRAS-wild type metastatic colorectal cancer, but eventually, resistance to this therapy emerges (Sforza et al, 2016; Bhattacharya 2023). Since sEVs from CRC cells have previously been reported to induce cetuximab resistance (Zhang et al, 2017; Yang et al, 2018), we set out to test whether HCT116 sEVs, and in particular Rab11a-exosomes, might mediate such effects.…”

Section: Resultsmentioning

confidence: 99%

Stress-induced Rab11a-exosomes induce AREG-mediated cetuximab resistance in colorectal cancer

Mason,

Marks,

Fan

et al. 2023

Preprint

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Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the Epidermal Growth Factor Receptor (EGFR) ligand, Amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.Graphical AbstractThis study highlights a clinically relevant mechanism in which stress-induced Rab11a-exosomes carrying the EGFR ligand, Amphiregulin (AREG) transfer drug resistance between genetically distinct colorectal cancer cells. Resistance to cetuximab, an anti-EGFR therapy, can be passed via Rab11a-exosomes from drug-resistant KRAS-mutant cells to previously drug-responsive KRAS-wild type cells. Unlike soluble AREG, Rab11a-exosome-associated AREG competes with cetuximab to activate EGFR signalling and promote EGFR-dependent outcomes, such as growth. This mechanism may support the co-operative evolution of clonal heterogeneity during tumour progression.

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“…In recent years, CDK4/6 inhibitors have attracted much attention due to their unique mechanism of action and have also achieved good efficacy in the treatment of many tumors. Studies[ 30 , 31 ] have reported that anti-EGFR treatment resistance mechanisms are associated with bypass activation, including the MEK-ERK pathway and the PI3K pathway, the activation of which further leads to an increase in cyclin D expression, resulting in cell proliferation. Sorah et al [ 32 ] reported the phase II Single-Arm Study about Palbociclib and Cetuximab rechallenge in patients with KRAS/NRAS/BRAF WT CRC treated with ≥ 2 lines of therapy and reported on a group of patients rechallenged with anti-EGFR-based treatment who had disease control for at least 4 mo on anti-EGFR therapy priorly.…”

Section: Treatments Targeting Ras Statusmentioning

confidence: 99%

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

Zhou,

Wu,

2024

World J Gastrointest Oncol

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More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.

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An empirical review on the resistance mechanisms of epidermal growth factor receptor inhibitors and predictive molecular biomarkers in colorectal cancer

Cited by 8 publications

References 104 publications

Stress‐induced Rab11a‐exosomes induce amphiregulin‐mediated cetuximab resistance in colorectal cancer

Stress‐induced Rab11a‐exosomes induce amphiregulin‐mediated cetuximab resistance in colorectal cancer

Stress-induced Rab11a-exosomes induce AREG-mediated cetuximab resistance in colorectal cancer

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

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