ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer

Lv, Zheng; Zhao, Kejia; Wei, Shiyou; Liu, Chengwu; Zhou, Jian‐Kang; Wu, Xia; Yang, Zhenyu; Yang, Yanbo; Peng, Yong; Cheng, Qing; Liu, Lunxu

doi:10.1080/2162402x.2020.1758003

Cited by 18 publications

(18 citation statements)

References 39 publications

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“…In our work, PD-L1 expression in HCC1937 and HCC1806 was significantly increased after combined treatment, but diminished in MDA-MB-231 and HCC1806 cells after single treatment with the ERK inhibitor. In concordance, Qian and colleagues showed a decreased PD-L1 mRNA expression after ERK1/2 inhibition in bladder cancer cells (Qian et al 2008), and Liu and coworkers confirmed a downregulation of PD-L1 expression and ERK phosphorylation in NSCLC cells after PD0325901 or U0126 treatment (Liu et al 2020). Several studies indicated an increased PD-L1 expression in TNBC compared to non-TNBC, though the results differed strongly (Barrett et al 2015;Bedognetti et al 2016;Gatalica et al 2014).…”

Section: Discussionmentioning

confidence: 82%

“…Downregulation of PD-L1 with siRNA was accompanied by downregulation of mesenchymal proteins and decreased phosphorylation of ERK and STAT3 (Cui et al 2021 ). Also, ERK mediates PD-L1 expression in NSCLC (non small cell lung carcinoma) cells with ROS1 fusion: Liu and coworker showed that both ERK phosphorylation and PD-L1 expression were down-regulated after treating HCC78 cells with PD0325901 or U0126 (Liu et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of PD-1/PD-L1 and ERK1/2 impede the proliferation of receptor positive and triple-negative breast cancer cell lines

Bräutigam

Kabore-Wolff

Hussain

et al. 2021

J Cancer Res Clin Oncol

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Purpose Triple-negative breast cancer (TNBC) is characterized by an unfavorable prognosis and missing systemic therapeutic approaches beside chemotherapy. Targeting the immune checkpoint PD-1/PD-L1 showed promising results in breast cancer and especially in TNBC. The extracellular signal-regulated kinase 1/2 (ERK1/2) is an important driver of carcinogenesis. Here, the effect of combined PD-1/PD-L1 and ERK1/2 inhibitor treatment is investigated of cell growth and intracellular impact of breast cancer cell lines. Methods The IC50 values of each inhibitor and the effect of combined treatment were determined in three TNBC cell lines of different subtypes and one non-TNBC cell line. Phospho-specific antibodies were used in western blot analyses to investigate an effect on ERK1/2 activation. Expressions of immune modulatory and cell cycle-associated genes were examined by quantitative reverse transcription PCR. Results Both inhibitors PD-1/PD-L1 and ERK1/2 impeded the proliferation of TNBC to a higher extent than of non-TNBC. By combined treatment, cell lines were inhibited either synergistically or additively. ERK1/2 and S6 phosphorylation were reduced and expressions of c-Fos and FosL were diminished after ERK1/2 inhibitor as single and combined treatment. Between genes involved in immune modulation, IL-8 was upregulated in TNBC cells after combined treatment. Conclusion In conclusion, combination of PD-1/PD-L1 and ERK1/2 inhibitors showed favorable effects for a new therapy strategy, with better results in TNBC cell lines than in non-TNBC cells. The effects have to be validated in models that can reflect the interaction between immune and tumor cells like the situation in the tumor micro-environment.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Inhibitors of PD-1/PD-L1 and ERK1/2 impede the proliferation of receptor positive and triple-negative breast cancer cell lines

Bräutigam

Kabore-Wolff

Hussain

et al. 2021

J Cancer Res Clin Oncol

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“…Non-crizotinib systemic therapies yielded mixed results within this cohort. Despite a high rate of PD-L1 expression reflecting a known association between ROS1-rearrangements and upregulated PD-L1 [29], response to and effectiveness of ICI in this cohort was limited, with outcomes significantly below those observed in similarly treated, but driver-mutation negative KEYNOTE-42 and 189 cohorts [30,31]. These findings support an emerging body of literature suggesting that ICI use-particularly ICI monotherapy-in ROS1-rearranged NSCLC may elicit an inconsistent and generally poor response [32], implying that PD-L1 expression alone may not be sufficient to predict response to ICI, especially in the presence of a driver mutation [33,34].…”

Section: Discussionmentioning

confidence: 99%

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort

et al. 2022

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The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014–2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.

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“…A recent study suggests that PD-L1/PD-1 blockade could be the second-line treatment option based on the correlation of ROS1 fusion with PD-L1 expression. 4 Two patients with ROS1 fusion have been reported to respond well to immunotherapy. 16 However, PD-L1 expression was upregulated in this ROS1 -rearranged NSCLC patient after ceritinib treatment but did not bring about a long-term benefit from ICT.…”

Section: Discussionmentioning

confidence: 99%

“… 3 Nonetheless, studies have demonstrated the correlation between ROS1 rearrangement and high programmed cell death ligand 1 (PD-L1) expression. 4 5 Whether ICI-based therapy is effective in patients following first-line targeted agents still needs more investigation.…”

Section: Introductionmentioning

confidence: 99%

Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient withROS1-rearranged lung adenocarcinoma

Yue

Qian

Chen

et al. 2021

J Immunother Cancer

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Patients with ROS1-rearranged non-small cell lung cancer (NSCLC) inevitably relapse after first-line targeted therapy with tyrosine kinase inhibitors. Efficacy of checkpoint inhibitor-based therapy on ROS1-positive NSCLC in second-line setting and change of immune factors during treatment are rarely studied. We report a ROS1-rearranged stage ⅢB lung adenocarcinoma patient who was resistant to ceritinib after developing a secondary ROS1 F2004L mutation. He received eight cycles of nivolumab plus chemotherapy and had an initial partial response, but brain metastases appeared in the seventh cycle. Lorlatinib was confirmed to have activity against CD74–ROS1 with F2004L in vitro, and was administered to this patient as the third-line therapy. The patient responded well to lorlatinib and had no relapse. We explored the tumor immune microenvironment (TIME) during immune-chemotherapy by multiplex immunohistochemistry, RNA sequencing, and multiplex plasma protein immunoassay. The results show that the TIME was active and plasma inflammatory factors were increased when the patient responded to immune-chemotherapy, while the plasma inhibitory checkpoint proteins, lymphocyte-activation gene 3, B and T lymphocyte attenuator, programmed cell death ligand 1 (PD-L1), and PD-1, were increased when the disease progressed. Moreover, the PD-L1 expression on tumor tissue was upregulated during treatment, predicting the limited benefit from immune-chemotherapy. This case report suggests that lorlatinib is a better choice than immune-chemotherapy in second-line setting for patients with similar genomic characteristics, and that monitoring the immune components during immunotherapy may help to predict disease response.

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ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer

Cited by 18 publications

References 39 publications

Inhibitors of PD-1/PD-L1 and ERK1/2 impede the proliferation of receptor positive and triple-negative breast cancer cell lines

Inhibitors of PD-1/PD-L1 and ERK1/2 impede the proliferation of receptor positive and triple-negative breast cancer cell lines

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort

Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient withROS1-rearranged lung adenocarcinoma

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