RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case Series of 14 Patients

Sarfaty, Michal; Moore, Assaf; Neiman, Victoria; Dudnik, Elizabeth; Ilouze, Maya; Gottfried, Maya; Katznelson, Rivka; Nechushtan, Hovav; Sorotsky, Hadas; Paz, Keren; Katz, Amanda; Sauté, Milton; Wolner, M.; Moskovitz, Mor; Miller, Vincent A.; Elvin, Julia A.; Lipson, Doron; Ali, Siraj M.; Gutman, Lior Soussan; Dvir, Addie; Gordon, Noa; Peled, Nir

doi:10.1016/j.cllc.2016.09.003

Cited by 26 publications

(23 citation statements)

References 17 publications

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“…KIF5B-RET studies in mammalian cells have shown similar strong upregulation of the SRC pathway (Lin et al, 2016). In addition analysis a cohort of patients with KIF5B-RET rearrangement (Sarfaty et al, 2016) shows frequent visceral metastases, which is consistent with our findings of increased SRC-dependent local invasion through invadopodia formation.…”

Section: Discussionsupporting

confidence: 91%

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Das

Cagan

2017

Cell Reports

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Summary Gene fusions are increasingly recognized as important cancer drivers. KIF5B-RET gene was recently identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation including invadopodia-like processes. Through a combination of genetic and biochemical studies we demonstrate that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB vesicle-dependent RET-SRC-EGFR-FGFR ‘signaling hub’. We demonstrate that drugs designed to inhibit RET alone work poorly in KIF5B-RET-transformed cells. However, combining the RET inhibitor sorafenib with drugs that target EGFR or microtubules or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility in exploring the full biology of fusions to identify rational therapeutic strategies.

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Section: Discussionsupporting

confidence: 91%

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Das

Cagan

2017

Cell Reports

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“…A recent study of tumors with RET fusions used cfDNA to identify several patients in their cohort. 36 As the current cohort of patients was selected based on a positive cfDNA ALK result, we do not have an accurate estimate for the false negative rate. Therefore, this testing should be viewed as a rule-in versus a rule-out test.…”

Section: Discussionmentioning

confidence: 99%

Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

McCoach

Blakely

Banks

et al. 2018

Clinical Cancer Research

142

124

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Purpose Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy. Experimental Design The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Results Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK positive patients had no history of targeted therapy (cohort 1) with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, 11 tissue insufficient). Follow-up of 3 of the 5 tissue negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 – 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR activating mutations, an ALK fusion was identified on progression (cohort 4) (4 STRN, 1 EML4; one both STRN and EML4), five harbored EGFR T790M. Conclusions In this cohort of cfDNA detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a non-invasive means of detecting targetable alterations, and characterizing resistance mechanisms on progression.

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“…Cytotoxic chemotherapy with CBDCA plus PEM was effective, whereas pembrolizumab therapy was not, despite high expression of PD‐L1. In general, ICIs are less effective in NSCLC with EGFR mutation, EML4‐ALK fusion, or other rare mutations . Sabari et al .…”

Section: Discussionmentioning

confidence: 99%

“…In general, ICIs are less effective in NSCLC with EGFR mutation, EML4-ALK fusion, or other rare mutations. 12,13 Sabari et al reported that 40% of the NSCLC patients with a MET exon 14 skipping mutation express high PD-L1 (> 50%) and that the overall response rate of patients treated by ICIs was as low as 33%. 14 We considered that this low efficacy of ICIs in those with both high PD-L1 expression and a MET exon 14 skipping mutation might be explained by a low tumor mutation burden (TMB).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of pembrolizumab for patients with both high PD‐L1 expression and an MET exon 14 skipping mutation: A case report

et al. 2019

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Pembrolizumab has become the standard first‐line treatment for non‐small cell lung cancer (NSCLC) patients with high PD‐L1expression. MET exon 14 skipping is a rare mutation typically found in older, female, and non‐smoking patients with NSCLC. Herein, we report the case of a 71‐year‐old non‐smoking woman who was diagnosed with NSCLC in the left lung. EGFR mutation and ALK fusion were not detected. Because the biopsy specimen showed high PD‐L1 expression with a tumor proportion score of 95%, pembrolizumab was introduced as first‐line therapy, but resulted in no clinical benefit. The patient was subsequently administered chemotherapy with carboplatin and pemetrexed, leading to remarkable tumor shrinkage. A next‐generation sequencing panel analysis revealed a MET exon 14 skipping mutation. Thus, pembrolizumab might not be effective for NSCLC patients with MET exon 14 skipping mutations, even if PD‐L1 expression is high.

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RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case Series of 14 Patients

Cited by 26 publications

References 17 publications

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

Efficacy of pembrolizumab for patients with both high PD‐L1 expression and an MET exon 14 skipping mutation: A case report

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