<scp><i>ROS1</i></scp> genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer

Akhoundova, Dilara; Hussung, Saskia; Sivakumar, Smruthy; Töpfer, Antonia; Rechsteiner, Markus; Kahraman, Abdullah; Arnold, Fabian; Angst, Florian; Britschgi, Christian; Zoche, Martin; Moch, Holger; Weber, Achim; Sokol, Ethan S.; Fritsch, Ralph

doi:10.1002/ijc.34257

Cited by 12 publications

(6 citation statements)

References 52 publications

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“…not been solved yet [31]. Point mutations including CD74-ROS1 L2026M mutation are important causes of crizotinib resistance [17].…”

Section: Discussionmentioning

confidence: 99%

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CD74–ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non‐small cell lung cancer cells

Xu,

Li,

et al. 2024

The FEBS Journal

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The treatment of non‐small cell lung cancer (NSCLC) patients harboring a proto‐oncogene tyrosine‐protein kinase c‐ros oncogene 1 (ROS1) fusion gene has greatly benefited from the use of crizotinib. However, drug resistance inevitably occurs after 1 year of treatment. Clinical studies have shown that patients with an L2026M mutation in the ROS1 kinase domain account for about 6% of the total number of crizotinib‐resistant cases, which is an important group that cannot be ignored. To explore the mechanism involved, we constructed the HLA class II histocompatibility antigen gamma chain (CD74)–ROS1 L2026M mutant gene by fusion polymerase chain reaction (PCR) and transfected it into H460 and A549 cells. We found that the invasion and metastasis abilities of drug‐resistant cells were increased. The results of monodansylcadaverine (MDC) staining, Acridine orange (AO) staining and western blot indicated that the autophagy level of CD74–ROS1 L2026M mutant NSCLC cells was increased compared with the CD74–ROS1 group, and the inhibition of autophagy could reverse the increased invasion and metastasis abilities caused by the L2026M mutation. In addition, the L2026M mutation led to excessive activation of the MEK/ERK pathway, and MEK inhibitors could reduce the autophagy level, invasion and metastasis abilities of cells; additionally, this process could be blocked by rapamycin, an activator of autophagy. Furthermore, crizotinib treatment activated expression of Src homology region 2 domain‐containing phosphatase‐2 (SHP2; also known as PTPN11) to upregulate the MEK/ERK pathway, and the combination of MEK inhibitors and crizotinib increased apoptosis compared with crizotinib alone. In conclusion, our results indicate that the MEK/ERK pathway mediates the induction of invasion, metastasis and crizotinib resistance through autophagy caused by CD74–ROS1 L2026M mutation in NSCLC cells, and targeting MEK could reverse these processes.

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“…not been solved yet [31]. Point mutations including CD74-ROS1 L2026M mutation are important causes of crizotinib resistance [17].…”

Section: Discussionmentioning

confidence: 99%

“…Although the life quality of ROS1 fusion gene positive NSCLC patients has been greatly improved with the use of crizotinib, the problem of drug resistance has not been solved yet [31]. Point mutations including CD74‐ROS1 L2026M mutation are important causes of crizotinib resistance [17].…”

Section: Discussionmentioning

confidence: 99%

CD74–ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non‐small cell lung cancer cells

Xu,

Li,

et al. 2024

The FEBS Journal

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“…Additionally, SRPK1 has been found to play an important role in the growth, metastasis, and transformation of tumors [28,29]. It is closely associated with the occurrence of various tumors, including but not limited to breast cancer [30,31], colorectal cancer [32], lung cancer [33], and cervical cancer [34]. Therefore, the function of the SRPK1 gene is not only important in normal cellular physiological processes but also significant in the occurrence and development of tumors.…”

Section: Discussionmentioning

confidence: 99%

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/β-Catenin and JAK-2/STAT-3 Signaling Pathways

Shi,

Sun,

Deng

et al. 2024

Biomedicines

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Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/β-catenin (wingless-int1/β-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of β-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/β-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

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“…ROS1 fusion, including SLC34A2-ROS1 fusion and GOPC-ROS1 fusion, occurs in 0.2%–2.4% of CRC cases 61 . Additionally, ROS1 is considered a driver in microsatellite stable CRC 65 , 66 . ALK inhibitors are expected to be used for the treatment of patients with ROS1 gene rearranged mCRC 57 , 61 , 67 .…”

Section: Fusion Genes Produced By Kinase Rearrangementmentioning

confidence: 99%

Progress in clinical diagnosis and treatment of colorectal cancer with rare genetic variants

Chen,

Gu,

et al. 2024

Cancer Biol Med

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Targeted therapy is crucial for advanced colorectal cancer (CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs, existing standard molecular pathological detection systems and therapeutic strategies can no longer meet the requirements for careful management of patients with advanced CRC. Thus, rare genetic variations require diagnosis and targeted therapy in clinical practice. Rare gene mutations, amplifications, and rearrangements are usually associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare genetic variations, in genes including erb-b2 receptor tyrosine kinase 2 (ERBB2), B-Raf proto-oncogene, serine/threonine kinase (BRAF), ALK receptor tyrosine kinase/ROS proto-oncogene 1, receptor tyrosine kinase (ALK/ROS1), neurotrophic receptor tyrosine kinases (NTRKs), ret proto-oncogene (RET), fibroblast growth factor receptor 2 (FGFR2), and epidermal growth factor receptor (EGFR), to enhance understanding and identify more accurate personalized treatments for patients with rare genetic variations.

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ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer

Cited by 12 publications

References 52 publications

CD74–ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non‐small cell lung cancer cells

CD74–ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non‐small cell lung cancer cells

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/β-Catenin and JAK-2/STAT-3 Signaling Pathways

Progress in clinical diagnosis and treatment of colorectal cancer with rare genetic variants

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