Emerging resistance pathways in lung cancer: what has ROS-1 taught us?

Alrifai, Doraid; Förster, Martin; Janes, Sam M.

doi:10.21037/tlcr.2017.11.13

Cited by 3 publications

(9 citation statements)

References 29 publications

(24 reference statements)

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“…given that most patients treated using this agent will acquire resistance 19 and that the duration of response to crizotinib cannot yet be predetermined and seems to have no relation to the ROS1 fusion partner 52 . Resistance to crizotinib, and resulting disease progression, comes about by a variety of mechanisms: development of secondary mutations within the kinase domain, which impedes drug binding 14 ; epithelial-to-mesenchymal transition 47,53 ; or upregulation and activation of compensatory pathways 14 such as EGFR, RAS, and KIT 19 .…”

Section: China: Efficacy Of Crizotinib and Pemetrexed-based Therapy I...mentioning

confidence: 99%

“…The most common secondary mutation, G2032R [c.6094G>A (p.Gly2032Arg)], accounts for 41% of identified secondary mutations 19 , and it is unclear whether crizotinib use selects for pre-existing resistant clones or whether the evolution of crizotinibresistant cells occurs during a period of exposure 19 . Given the diverse mechanisms that lead to crizotinib resistance, sequential treatment targeting crizotinib-resistant cells, or dual inhibition of ROS1 and potentially upregulated pathways, might show efficacy in minimizing and managing resistance to crizotinib 14 .…”

Section: Meeting the Challenge Of Progressive Disease Acquired Resist...mentioning

confidence: 99%

“…Interchromosomal -and occasionally intrachromosomal-rearrangements of ROS1 result in gene fusions involving the 3′ region of ROS1, including the kinase domain, and several different 5′ fusion partners 2,6,12 , of which 26 have been identified to date 13 . All ROS1 fusions show conservation of the ros1 kinase domain 2,12 and lead to tyrosine kinase activation 2,12,13 , a multi-use intracellular pathway involved in the upregulation of shp-1 and shp-2 and resultant activation of the pi3k/akt/mtor, jak/stat, and makp/erk pathways, which act in concert to promote cell survival and proliferation 7,14 .…”

Section: Introductionmentioning

confidence: 99%

“…Based on those results and preliminary data from a single-arm phase ii study (profile 1005), accelerated regulatory approval for the use of crizotinib in ALK-positive locally advanced or metastatic nsclc, was awarded by the U.S. Food and Drug Administration and Health Canada in 2011 and 2012 respectively 6,8,14,22,23 . Subsequently, both in vivo and in vitro, crizotinib was found to be a highly robust inhibitor of the ros1 fusion protein, showing up to 5 times greater potency in the suppression of ros1 activity and downstream signalling-and resultant superior inhibition of ros1-driven tumour growth-than what had been observed in ALK-rearranged tumours 19 .…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent clinical trials of crizotinib in ROS1-rearranged nsclc yielded response rates of 70% -80%, and approval for crizotinib in the management of ROS1-positive locally advanced or metastatic nsclc was granted in 2016 by the U.S. Food and Drug Administration and in 2017 by Health Canada for use in the first-and subsequent-line settings 24 . To date, crizotinib remains the only approved targeted agent for ROS1-rearranged advanced nsclc 14,20 , and ROS1-rearranged nsclc is now the 3rd genetically distinct population of nsclc that can be managed through approved, effective targeted therapy 7,25 .…”

Section: Introductionmentioning

confidence: 99%

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Crizotinib Inhibition of ROS1-Positive Tumours in Advanced Non-Small-Cell Lung Cancer: A Canadian Perspective

Dg¹,

Agulnik²,

Albadine³

et al. 2019

Current Oncology

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The ROS1 kinase is an oncogenic driver in non-small-cell lung cancer (NSCLC). Fusion events involving the ROS1 gene are found in 1%–2% of NSCLC patients and lead to deregulation of a tyrosine kinase–mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of NSCLC, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology. Targeted inhibition of the aberrant ros1 kinase with crizotinib is associated with increased progression-free survival (PFS) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged NSCLC, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement. Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced NSCLC, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced NSCL. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop.

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Section: China: Efficacy Of Crizotinib and Pemetrexed-based Therapy I...mentioning

confidence: 99%

Section: Meeting the Challenge Of Progressive Disease Acquired Resist...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Crizotinib Inhibition of ROS1-Positive Tumours in Advanced Non-Small-Cell Lung Cancer: A Canadian Perspective

Dg¹,

Agulnik²,

Albadine³

et al. 2019

Current Oncology

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Favorable response to PD-1 receptor inhibitor pembrolizumab as a third-line therapy in ROS1-rearranged advanced lung cancer: A case report and review of the literature

Chaudhry¹,

Schuppe

Burke

et al. 2022

Current Problems in Cancer: Case Reports

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From targeted therapy to a novel way: Immunogenic cell death in lung cancer

Xiong

Zhang

et al. 2022

Front. Med.

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Lung cancer (LC) is one of the most incident malignancies and a leading cause of cancer mortality worldwide. Common tumorigenic drivers of LC mainly include genetic alterations of EGFR, ALK, KRAS, BRAF, ROS1, and MET. Small inhibitory molecules and antibodies selectively targeting these alterations or/and their downstream signaling pathways have been approved for treatment of LC. Unfortunately, following initial positive responses to these targeted therapies, a large number of patients show dismal prognosis due to the occurrence of resistance mechanisms, such as novel mutations of these genes and activation of alternative signaling pathways. Over the past decade, it has become clear that there is no possible cure for LC unless potent antitumor immune responses are induced by therapeutic intervention. Immunogenic cell death (ICD) is a newly emerged concept, a form of regulated cell death that is sufficient to activate adaptive immune responses against tumor cells. It transforms dying cancer cells into a therapeutic vaccine and stimulates long-lasting protective antitumor immunity. In this review, we discuss the key targetable genetic aberrations and the underlying mechanism of ICD in LC. Various agents inducing ICD are summarized and the possibility of harnessing ICD in LC immunotherapy is further explored.

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Emerging resistance pathways in lung cancer: what has ROS-1 taught us?

Cited by 3 publications

References 29 publications

Crizotinib Inhibition of ROS1-Positive Tumours in Advanced Non-Small-Cell Lung Cancer: A Canadian Perspective

Crizotinib Inhibition of ROS1-Positive Tumours in Advanced Non-Small-Cell Lung Cancer: A Canadian Perspective

Favorable response to PD-1 receptor inhibitor pembrolizumab as a third-line therapy in ROS1-rearranged advanced lung cancer: A case report and review of the literature

From targeted therapy to a novel way: Immunogenic cell death in lung cancer

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