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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
RET rearrangements have been reported in approximately 1–2% of all NSCLC patients [74–76], and in up to 16% of NSCLC cases negative for other mutations [77]. RET rearrangements are largely mutually exclusive with genetic alterations in other oncogenic drivers, such as EGFR, KRAS, ALK, and ROS1 [76]. One particular driver mutation, KIF5B-RET, has been identified in majority of lung carcinomas with RET rearrangement [74].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Following these exceptional results, Pfizer granted a sub-license to Abbott to develop a companion diagnostic test for selecting patients to be treated with crizotinib, and in 2011 Abbott launched the Vysis ALK Break Apart FISH Probe Kit (Figure 6.60A) for use in identifying the 3–5% of NSCLC patients with an ALK gene rearrangement suitable for treatment with crizotinib. An alternative test, the ZytoLightTM SPEC ALK/EML4 TriCheckTM Probe, was developed by ZytoVision Inc. This probe is designed to detect and discriminate between inversions, leading to fusions with Echinoderm Microtubule-Associated Protein-Like 4 (EML4), and translocations affecting ALK but not EML4, such as ALK-KIF5B or ALK-TFG (Figure 6.60B).
Lung Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
RET-rearrangements are seen in 1% to 2% of NSCLCs. The most frequent fusion partner is KIF5B (72%).43 Although no drugs have been approved for RET-rearranged NSCLCs, several multitargeted RET inhibitors (cabozantinib, lenvatinib, and vandetanib) have been approved for medullary thyroid cancer, which commonly harbors activating RET point mutations. BLU-667 and LOXO-292 are newer compounds, which have demonstrated impressive activity and tolerability in early-phase studies of RET-rearrangement-positive NSCLC.
Mesenchymal stem cells shuttling miR-503 via extracellular vesicles enhance glioma immune escape
Published in OncoImmunology, 2022
Xiao-Song Wang, Xiao-Jun Yu, Kang Wei, Shan-Xi Wang, Qi-Kun Liu, Ying-Guang Wang, Han Li, Cheng Huang
Extracellular vesicles (EVs), nano-sized vesicles (30 to 100 nm in diameter), have been recognized as critical regulators of brain tumors by the delivery of oncogenic proteins, receptors, and small RNAs that may support brain tumor progression, including glioma.5 EVs have also shown to affect host anti-tumor immune response and tumor cell immune escape in glioma.6 EVs are released by both normal and diseased cells including mesenchymal stem cells (MSCs).7 The pluripotency and immunoregulation of MSCs can facilitate tumor development, progression and even metastasis in glioma.8 microRNA-503 (miR-503) serves as an upregulated miR in glioma from previous evidence and functionally facilitates glioma cell proliferation.9 A web-available bioinformatic prediction shows kinesin-1 (KIF5) as a putative target gene of miR-503. KIF5 family members are microtubule-dependent molecular motors that consist of KIF5A, KIF5B, and KIF5C. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system, which is required for neuronal function.10 Mutation of KIF5A is linked with the pathogenesis of neurological diseases.11 Evidence shows that peripheral immunization by combining interleukin-7 (IL-7)- and interferon-gamma (IFNγ)-producing tumor cells prolong survival in two rat glioma models.12 Herein, we proposed a prevailing hypothesis that MSC-derived EVs transfer miR-503 to glioma cells, and overexpressed miR-503 enhances glioma immune escape.
Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome
Published in OncoImmunology, 2022
Tianying Su, George E. Duran, Alexa C. Kwang, Nirasha Ramchurren, Steven P. Fling, Youn H. Kim, Michael S. Khodadoust
Distinguishing malignant from nonmalignant T-cells in CTCL poses a major challenge in identifying potential biomarkers of response to immunotherapy. High-dimensional analysis such as mass cytometry or highly multiplexed imaging can more reliably identify malignant T-cells, but still may be imperfect in resolving CTCL cells from similar CD4 T-cell subsets. We used single-cell analysis with TCR sequencing to better resolve tumor-intrinsic and tumor-extrinsic features. Three Sézary cell-intrinsic markers were discovered through this approach. High expression of HSD17B11 and KIF5B was associated with responding patient. The short-chain alcohol dehydrogenase gene HSD17B11 has previously been identified as a serologic tumor antigen in CTCL with 4 out of 6 patients demonstrating serological reactivity against the antigen.34KIR3DL2 has consistently been found to be overexpressed in Sézary cells.35KIR3DL2, according to previous studies, helps Sézary cells avoid activation-induced cell death.36,37 Expressions of KIR3DL2 and PD-1 have been proposed to define three subclasses of Sézary syndrome with distinct skin immune microenvironments including higher numbers of reactive CD8 + T-cells in the setting of low KIR3DL2 expression.38 Since low expression of KIR3DL2 was associated with response, our results raise the possibility that treatment with anti-KIR3DL2 treatment such as lacutamuab39 could synergize with pembrolizumab therapy.
Fusion proteins in lung cancer: addressing diagnostic problems for deciding therapy
Published in Expert Review of Anticancer Therapy, 2021
Federica Zito Marino, Greta Alì, Francesco Facchinetti, Luisella Righi, Gabriella Fontanini, Giulio Rossi, Renato Franco
The proto-oncogene RET is located on chromosome 10q11.2 and encodes for the RET transmembrane RTK glycoprotein [65–67]. Oncogenic activation of RET can occur through two primary mechanisms: chromosomal rearrangements, causing a fused-activated protein and mutations, able to activate directly or indirectly the kinase [68–71]. The activation leads to a signaling cascade triggering downstream signals, including MAPK and PI3K-AKT pathways, and promotes cancer initiation and progression [72]. RET gene fusions have been reported in 1 to 2% of NSCLC and in 10 to 20% of sporadic papillary thyroid cancer [73,74]. The kinesis family 5B (KIF5B) and the coiled-coil domain-containing protein 6 (CCDC6) genes are the most frequently reported intrachromosomal RET fusion partners in NSCLCs. Other upstream fusion partners have been identified in NSCLC; all of these fusion proteins have a dimerization domain inducing ligand-independent activation of the RET kinase [75–77].