Expression of neurofibromin 1 in colorectal cancer and cetuximab resistance

Tak, Eunyoung; Kim, Minhee; Cho, Young-Ra; Choi, Sun Young; Kim, Jihun; Han, Buhm; Kim, Hyung‐Don; Jang, Chloe Soohyun; Kim, Jeong Eun; Hong, Yong Sang; Kim, Sun Young; Kim, Tae Won

doi:10.3892/or.2021.8226

Cited by 3 publications

(4 citation statements)

References 49 publications

(61 reference statements)

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“…The heterozygous inactivating neurofibromin 1 ( NF1 ) mutation discovered in the primary resistant tumour BoC109, is likely to contribute to a reduced sensitivity of the vertical inhibition by reducing the effect of cetuximab on RAS signaling. This is supported by data from the cetuximab‐resistant CRC cell line KM12C harboring a NF1 truncating mutation with a similar allele frequency, in which restoration of the NF1 function reduced MEK and ERK phosphorylation as well as cell proliferation and increased cetuximab induced apoptosis [51]. Gene expression analyses, in turn, revealed in agreement with the observed DUSP6 rise in the majority of resistant tumours, that re‐activation of the RAS pathway is critical for developing primary and SR (Fig.…”

Section: Discussionmentioning

confidence: 72%

Lasting response by vertical inhibition with cetuximab and trametinib in KRAS‐mutated colorectal cancer patient‐derived xenografts

Reissig,

Ladigan‐Badura,

Steinberg

et al. 2023

Molecular Oncology

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Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS‐pathway by targeting epidermal growth factor receptor (EGFR) and mitogen‐activated protein kinase kinase (MEK) in patient‐derived xenograft (PDX) tumours with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; ≤ − 30%), stable disease (SD; between −30% and +20%) or progressive disease (PD; ≥ + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.

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Section: Discussionmentioning

confidence: 72%

Lasting response by vertical inhibition with cetuximab and trametinib in KRAS‐mutated colorectal cancer patient‐derived xenografts

Reissig,

Ladigan‐Badura,

Steinberg

et al. 2023

Molecular Oncology

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“…Primary antibodies included caspase-3 or cleaved (Asp175) caspase-3 (Cell Signaling Technology). To quantify apoptosis in intestinal tissue, the ratio of cleaved caspase-3 to total caspase-3 was used 32 …”

Section: Methodsmentioning

confidence: 99%

“…To quantify apoptosis in intestinal tissue, the ratio of cleaved caspase-3 to total caspase-3 was used. 32 …”

Section: Methodsmentioning

confidence: 99%

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model

et al. 2023

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Objective: To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF). Background: SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy. Methods: Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n = 6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/ EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline. Results: ILC animals demonstrated a 19% greater reduction in PN calories (P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P = 0.03) and 1.9-fold higher crypt cell proliferation (P = 0.02) compared with controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 (P = 0.02), eicosapentaenoic acid (P < 0.0001), docosahexaenoic acid (P = 0.004), vitamin A (P = 0.02), low-density lipoprotein (P = 0.02), and high-density lipoprotein (P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups. Conclusions: ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF.

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“…Anti-EGFR antibodies, such as cetuximab or panitumumab, have been demonstrated to be effective against RAS oncogene wild-type mCRC. However, patients will eventually develop drug resistance and further disease progression will occur regardless of the initial efficacy (6).…”

Section: Exosomes Derived From Mdr Cells Induce Cetuximab Resistance ...mentioning

confidence: 99%

Exosomes derived from MDR cells induce cetuximab resistance in CRC via PI3K/AKT signaling‑mediated Sox2 and PD‑L1 expression

et al. 2023

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The anti-EGFR antibody cetuximab is used as a first-line targeted therapeutic drug in colorectal cancer. It has previously been reported that the efficacy of the EGFR antibody cetuximab is limited by the emergence of acquired drug resistance. In our previous study the transmissibility effect of exosomes from drug resistant tumor cells to sensitive tumor cells was identified. It can therefore be hypothesized that drug resistant cells might affect neighboring and distant cells via regulation of exosome composition and behavior. However, the mechanism of exosomes in KRAS-wild-type colorectal cancer (CRC) remains unknown. In the present study, functional analysis of overall survival post-diagnosis in patients with KRAS wild-type and those with mutant CRC was performed using human CRC specimens. Furthermore, it was demonstrated that multidrug resistance (MDR) cancer cell-derived exosomes were potentially a key factor, which promoted cetuximab-resistance in CRC cells and reduced the inhibitory effect of cetuximab in CRC xenograft models. The Cell Counting Kit-8 and colony formation assays were performed to assess the effects of exosomes derived from CRC/MDR cells on cetuximab resistance. Sphere formation assay results demonstrated that exosomes derived from CRC/MDR cells altered the self-renewal and multipotential ability of stem-cell-associated markers and facilitated resistance to cetuximab in cetuximab-sensitive cells. Furthermore, exosomes derived from CRC/MDR cells decreased sensitivity to cetuximab via the activation of PI3K/AKT signaling, which promoted Sox2 and programmed death-ligand 1 (PD-L1) mRNA and protein expression according to reverse transcription-quantitative PCR, western blotting and immunohistochemistry analyses, as well as apoptosis resistance both in vitro and in vivo according to a TUNEL assay. In conclusion, the results of the present study demonstrated that exosomes derived from CRC/MDR cells may promote cetuximab resistance in KRAS wild-type cells via activation of the PI3K/AKT signaling pathway-mediated expression of Sox2 and PD-L1, which will be useful for investigating a potential clinical target in predicting cetuximab resistance.

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Expression of neurofibromin 1 in colorectal cancer and cetuximab resistance

Cited by 3 publications

References 49 publications

Lasting response by vertical inhibition with cetuximab and trametinib in KRAS‐mutated colorectal cancer patient‐derived xenografts

Lasting response by vertical inhibition with cetuximab and trametinib in KRAS‐mutated colorectal cancer patient‐derived xenografts

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model

Exosomes derived from MDR cells induce cetuximab resistance in CRC via PI3K/AKT signaling‑mediated Sox2 and PD‑L1 expression

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