Concurrent ROS1 gene rearrangement and KRAS mutation in lung adenocarcinoma: <scp>A</scp> case report and literature review

Zhu, You‐cai; Lin, Xueping; Li, Xiaofeng; Wu, Lei; Chen, Huafei; Wang, Wenxian; Xu, C.; Jianfa, Shen; Wei, Jianguo; Du, Ke

doi:10.1111/1759-7714.12518

Cited by 27 publications

(24 citation statements)

References 20 publications

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“…We found that MAPK pathway activation is necessary and sufficient for survival of cells expressing SDC4-ROS1 and SLC34A2-ROS1, suggesting MAPK pathway reactivation may be a mechanism of resistance to crizotinib monotherapy. Consistent with this notion, there are limited reports of RAS-activating mutations or upregulation driving resistance to crizotinib in the setting of ROS1 fusion-driven cancers (49,50). Identification of the downstream pathways activated by an oncogene could be critical to predict what pathway a tumor may reactivate during the evolution of resistance, as we showed in EML4-ALK NSCLC (20).…”

Section: Discussionsupporting

confidence: 59%

Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

et al. 2019

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Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here, we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced relocalization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins. Significance: ROS1 fusion oncoproteins exhibit differential activation of MAPK signaling according to subcellular localization, with ROS1 fusions localized to endosomes, the strongest activators of MAPK signaling.

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Section: Discussionsupporting

confidence: 59%

Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

et al. 2019

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“…In our cohort, two octogenarian males harbored a ROS1 translocation, and both had concurrent clinically relevant mutations ( ROS1 + / KRAS + and ROS1 + / NRAS + ). Similar anecdotal cases of concurrent ROS1 rearrangements and KRAS mutations were recently reported [21,22], whereas no cases of ROS1 translocations and NRAS variants have been described so far. ROS1 gene rearrangements could be targeted by TKIs, but KRAS / NRAS gene point mutations could lead to ineffective inhibition through inactivation of the RAF/MEK/ERK signaling pathway.…”

Section: Discussionsupporting

confidence: 78%

Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients

Fumagalli

Catania

Ranghiero

et al. 2019

JCM

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Background: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role of biologically driven therapies is still underrated. Methods: A single-institution cohort of 76 NSCLCs from octogenarian patients was submitted to molecular analysis using a next-generation sequencing (NGS) multigene panel, fluorescence in situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1 assessment. Treatment and clinical outcome data were available for 33 patients. Results: Most cases (n = 66, 87%) harbored at least one genomic alteration. EGFR and KRAS mutations were detected in 18 (24%) and 20 (26%) patients, respectively. No ALK alterations were found, but in two patients ROS1 translocation was identified. Of 22 cases tested, 17 were positive for PD-L1 staining. Octogenarian patients who received tyrosine kinase inhibitors (TKIs) based on molecular analysis showed clinical benefits, with long progression-free survival as expected in TKI-treated younger cohorts. Conclusions: This study highlights the utility of molecular profiling in all advanced-stage NSCLCs, regardless of the age at diagnosis, to drive personalized treatment. The prevalence of druggable alterations and the clinical benefits obtained by biologically-driven therapies in octogenarians were comparable to those of the younger NSCLC population.

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“…RAS-MAPK pathway hyperactivation has an established role in promoting resistance to EGFR, ALK, BRAF, and ROS1 targeted therapies via diverse mechanisms including KRAS amplification and KRAS, BRAF, and NF1 mutations (32)(33)(34)(35)(36)(37)(38)(39)(40). While KRAS amplification has also recently been reported at acquired MET TKI resistance in METex14-mutated NSCLC (10), the broader role of compensatory genomic events providing signaling pathway re-activation remains less well-understood in METex14mutated NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

Rotow

Gui

et al. 2018

Preprint

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Abstract:While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, their long-term survival is limited by drug resistance. The molecular basis for this resistance remains incompletely understood. Through targeted sequencing analysis of cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14 NSCLC, we find prominent co-occurring RAS pathway gene alterations (e.g. in KRAS/NRAS, NF1). Clinical resistance to MET TKI treatment was associated with the presence of these co-occurring alterations. In a new preclinical model expressing a METex14 mutation, KRAS overexpression promoted MET TKI resistance, which was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib. Our study provides a genetic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy to enhance clinical outcomes. Statement of Significance:This report describes targeted sequencing of the largest reported cohort of advanced-stage NSCLC with a MET exon 14 skipping mutation. The data uncover certain RAS pathway genetic alterations as potential mediators of MEK TKI resistance, which could be overcome by MEK and MET co-inhibition in NSCLC.Introduction:

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Concurrent ROS1 gene rearrangement and KRAS mutation in lung adenocarcinoma: A case report and literature review

Cited by 27 publications

References 20 publications

Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins

Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

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