BCL6 confers KRAS-mutant non–small-cell lung cancer resistance to BET inhibitors

Guo, Jiawei; Liu, Yanan; Lv, Jing; Zou, Bin; Chen, Zhi; Li, Kun; Juanjuan, Feng; Cai, Zhenyu; Wei, Lai; Liu, Mingyao; Pang, Xiufeng

doi:10.1172/jci133090

Cited by 36 publications

(47 citation statements)

References 61 publications

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“…Our results were conceptually in line with recent findings showing that BCL6 enabled heat stress tolerance in vertebrates (Fernando et al, 2019) and conferred tyrosine kinase inhibitor resistance in Ph + acute lymphoblastic leukemia (Duy et al, 2011). As reported in our recent work (Guo et al, 2021), BCL6 activation attenuated the antitumor efficacy of clinical BET inhibitors in KRAS-mutant lung cancers. Combining these findings together, we speculate that BCL6 may functionally program tumor pro-survival signals in drug response and can be used as a predictive biomarker for therapy resistance.…”

Section: Discussionsupporting

confidence: 93%

“…The aberrant expression of BCL6 can be provoked in leukemia cells in response to the tyrosine kinase inhibitor imatinib (Duy et al, 2011). Our recent work additionally revealed that an increased expression of BCL6 largely contributes to the resistance of KRAS-mutant lung cancer clinical BET inhibitors (Guo et al, 2021). Given the fact that BCL6 plays an emerging role in DNA damage tolerance and drug responses, we hypothesized that BCL6 might drive cancer cell resistance to genotoxic agents.…”

Section: Introductionmentioning

confidence: 97%

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The Oncoprotein BCL6 Enables Cancer Cells to Evade Genotoxic Stress

Pang

Juanjuan

et al. 2021

Preprint

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Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, the clinical benefits are often countered by a rapid tumor adaptive response. Here, we report that oncoprotein B cell lymphoma 6 (BCL6) is a core component that confers tumor adaptive resistance to genotoxic stress. Multiple genotoxic agents promoted BCL6 transactivation, which was positively correlated with a weakened therapeutic efficacy and a worse clinical outcome. Mechanistically, we discovered that treatment with the genotoxic agent etoposide led to the transcriptional reprogramming of multiple pro-inflammatory cytokines, among which the interferon-α and interferon-γ responses were substantially enriched in resistant cells. Our results further revealed that the activation of interferon/signal transducer and activator of transcription 1 axis directly upregulated BCL6 expression. The increased expression of BCL6 further repressed the tumor suppressor PTEN and consequently enabled resistant cancer cell survival. Accordingly, the targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. Our findings highlight the importance of BCL6 signaling in conquering tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 97%

The Oncoprotein BCL6 Enables Cancer Cells to Evade Genotoxic Stress

Pang

Juanjuan

et al. 2021

Preprint

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“…We found that chemotherapy-mediated transcriptional reprogramming of pro-inflammatory cytokines transactivated the STAT1-BCL6-PTEN axis, therefore protecting solid tumors from cell death. As reported in our recent work ( Guo et al, 2021 ), BCL6 activation attenuated the antitumor efficacy of clinical BET inhibitors in KRAS -mutant lung cancer. Our current work, along with the recently published studies, suggest a crucial role of BCL6 in rendering tumor cells more tolerant to treatments and a model in which multiple factors may contribute to BCL6 upregulation and BCL6-mediated signaling during this process.…”

Section: Discussionsupporting

confidence: 77%

“…The aberrant expression of BCL6 can be provoked in leukemia cells in response to the tyrosine kinase inhibitor imatinib ( Duy et al, 2011 ). Our recent work additionally revealed that an increased expression of BCL6 largely contributes to the resistance of KRAS -mutant lung cancer to clinical BET inhibitors ( Guo et al, 2021 ). However, the role and underlying mechanisms of BCL6 in chemo-sensitization of solid tumors remain elusive.…”

Section: Introductionmentioning

confidence: 99%

The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress

Liu

Juanjuan

Yuan

et al. 2022

eLife

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Genotoxic agents remain the mainstay of cancer treatment. Unfortunately, the clinical benefits are often countered by a rapid tumor adaptive response. Here, we report that the oncoprotein B cell lymphoma 6 (BCL6) is a core component that confers solid tumor adaptive resistance to genotoxic stress. Multiple genotoxic agents promoted BCL6 transactivation, which was positively correlated with a weakened therapeutic efficacy and a worse clinical outcome. Mechanistically, we discovered that treatment with the genotoxic agent etoposide led to the transcriptional reprogramming of multiple pro-inflammatory cytokines, among which the interferon-α and interferon-γ responses were substantially enriched in resistant cells. Our results further revealed that the activation of interferon/signal transducer and activator of transcription 1 axis directly upregulated BCL6 expression. The increased expression of BCL6 further repressed the tumor suppressor PTEN and consequently enabled resistant cancer cell survival. Accordingly, targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. Our findings highlight the importance of BCL6 signaling in conquering solid tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy.

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“…From a practical point of view, early identification of some of these different mechanisms of resistance can allow alternative treatments to NS-NSCLC harboring a KRAS G12C mutation to be proposed. Finally, among one of the recently identified mechanisms, BCL6 expression seems to be an important cause of resistance [ 163 ]. As consequences of these different mechanisms of resistance, many clinical trials are ongoing or are going to soon start combining a KRAS G12C inhibitor and different other therapeutic agents, some of which will later be detailed in the perspectives section [ 164 ].…”

Section: Resistance Mechanisms Induced In Non-small Cell Lung Carcino...mentioning

confidence: 99%

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

Bontoux

Hofman

Brest

et al. 2022

Cancers

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KRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinomas (NS-NSCLC), notably in lung adenocarcinomas. In most cases, these mutations are mutually exclusive, with different genomic alterations currently known to be sensitive to therapies targeting EGFR, ALK, BRAF, ROS1, and NTRK. Recently, several promising clinical trials targeting KRAS mutations, particularly for KRAS G12C-mutated NSCLC, have established new hope for better treatment of patients. In parallel, other studies have shown that NSCLC harboring co-mutations in KRAS and STK11 or KEAP1 have demonstrated primary resistance to immune checkpoint inhibitors. Thus, the assessment of the KRAS status in advanced-stage NS-NSCLC has become essential to setting up an optimal therapeutic strategy in these patients. This stimulated the development of new algorithms for the management of NSCLC samples in pathology laboratories and conditioned reorganization of optimal health care of lung cancer patients by the thoracic pathologists. This review addresses the recent data concerning the detection of KRAS mutations in NSCLC and focuses on the new challenges facing pathologists in daily practice for KRAS status assessment.

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BCL6 confers KRAS-mutant non–small-cell lung cancer resistance to BET inhibitors

Cited by 36 publications

References 61 publications

The Oncoprotein BCL6 Enables Cancer Cells to Evade Genotoxic Stress

The Oncoprotein BCL6 Enables Cancer Cells to Evade Genotoxic Stress

The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

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