Targeting ROS1 rearrangements in non-small cell lung cancer with crizotinib and other kinase inhibitors

Sehgal, Kartik; Patell, Rushad; Rangachari, Deepa; Costa, Daniel B.

doi:10.21037/tcr.2018.08.11

Cited by 52 publications

(47 citation statements)

References 25 publications

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“…In fact, crizotinib has been FDA-approved for the treatment of ROS1-positive NSCLC, increasing patient survival [40]. However, as for other tyrosine kinase inhibitors, the majority of patients progressively develop resistance to crizotinib [89][90][91]. Herein, we propose using active immunotherapy to induce the patient's own immune system to develop a long-lasting anti-tumor immune response against ROS1, as an alternative treatment.…”

Section: Discussionmentioning

confidence: 99%

Immunization against ROS1 by DNA Electroporation Impairs K-Ras-Driven Lung Adenocarcinomas

et al. 2020

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Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide. Despite the introduction of tyrosine kinase inhibitors and immunotherapeutic approaches, there is still an urgent need for novel strategies to improve patient survival. ROS1, a tyrosine kinase receptor endowed with oncoantigen features, is activated by chromosomal rearrangement or overexpression in NSCLC and in several tumor histotypes. In this work, we have exploited transgenic mice harboring the activated K-Ras oncogene (K-RasG12D) that spontaneously develop metastatic NSCLC as a preclinical model to test the efficacy of ROS1 immune targeting. Indeed, qPCR and immunohistochemical analyses revealed ROS1 overexpression in the autochthonous primary tumors and extrathoracic metastases developed by K-RasG12D mice and in a derived transplantable cell line. As proof of concept, we have evaluated the effects of the intramuscular electroporation (electrovaccination) of plasmids coding for mouse- and human-ROS1 on the progression of these NSCLC models. A significant increase in survival was observed in ROS1-electrovaccinated mice challenged with the transplantable cell line. It is worth noting that tumors were completely rejected, and immune memory was achieved, albeit only in a few mice. Most importantly, ROS1 electrovaccination was also found to be effective in slowing the development of autochthonous NSCLC in K-RasG12D mice.

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Section: Discussionmentioning

confidence: 99%

Immunization against ROS1 by DNA Electroporation Impairs K-Ras-Driven Lung Adenocarcinomas

et al. 2020

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“…A ROS1 ‐receptor tyrosine kinase gene rearrangement occurs in 1% to 2% of patients who have NSCLC, and approximately 36% of these patients present with BMs. First‐line therapies include crizotinib and ceritinib, and entrectinib recently gained US Food and Drug Administration approval, although evidence of intracranial activity of these agents in this patient population is limited, and CNS‐only disease progression rates on crizotinib are as high as 63% . Patients experiencing CNS disease progression on crizotinib should be considered for upfront BM‐directed therapy.…”

Section: Systemic Treatment Of Brain Metastasesmentioning

confidence: 99%

“…Patients experiencing CNS disease progression on crizotinib should be considered for upfront BM‐directed therapy. In the setting of extensive extracranial disease, however, initiating lorlatinib with close surveillance can be considered because there is evidence of intracranial activity in this setting …”

Section: Systemic Treatment Of Brain Metastasesmentioning

confidence: 99%

“…First-line therapies include crizotinib and ceritinib, and entrectinib recently gained US Food and Drug Administration approval, although evidence of intracranial activity of these agents in this patient population is limited, and CNS-only disease progression rates on crizotinib are as high as 63%. 39,40 Patients experiencing CNS disease progression on crizotinib should be considered for upfront BM-directed therapy. In the setting of extensive extracranial disease, however, initiating lorlatinib with close surveillance can be considered because there is evidence of intracranial activity in this setting.…”

Section: Anaplastic Lymphoma Kinase and Ros1 Translocationsmentioning

confidence: 99%

“…In the setting of extensive extracranial disease, however, initiating lorlatinib with close surveillance can be considered because there is evidence of intracranial activity in this setting. 39…”

Section: Anaplastic Lymphoma Kinase and Ros1 Translocationsmentioning

confidence: 99%

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Current multidisciplinary management of brain metastases

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et al. 2020

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Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late‐stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole‐brain radiation therapy, surgical resection, laser‐interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune‐checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.

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ALK/multikinase Inhibitors

2023

Molecules Engineered Against Oncogenic Proteins and Cancer

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Targeting ROS1 rearrangements in non-small cell lung cancer with crizotinib and other kinase inhibitors

Cited by 52 publications

References 25 publications

Immunization against ROS1 by DNA Electroporation Impairs K-Ras-Driven Lung Adenocarcinomas

Immunization against ROS1 by DNA Electroporation Impairs K-Ras-Driven Lung Adenocarcinomas

Current multidisciplinary management of brain metastases

ALK/multikinase Inhibitors

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