P14.26 Diminished Efficacy of PD-(L)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma is Impacted by KRAS Mutation Status

Ricciuti, Biagio; Arbour, Kathryn C.; Lin, Jennifer Y.; Vajdi, Amir; Tolstorukov, Michael Y.; Hong, Lingzhi; Zhang, J.; Li, Y.; Cherniack, Andrew D.; Recondo, Gonzálo; Rizvi, Hira; Egger, Jacklynn V.; Plodkowski, Andrew J.; Khosrowjerdi, S.; Digumarthy, Subba R.; Vaz, Nuno; Park, H.; Nishino, Mizuki; Sholl, Lynette M.; Barbie, David A.; Altan, Mehmet; Heymach, John V.; Skoulidis, Ferdinandos; Gainor, Justin F.; Hellmann, M.; Awad, Mark M.

doi:10.1016/j.jtho.2021.01.532

Cited by 12 publications

(7 citation statements)

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“…Arbour et al analyzed co-occurring the genetic alterations of 330 patients with KRAS -mutant NSCLC by NGS and found that KEAP1-NRF2 alterations occurred in 27% of the patients that had shorter OS from the initiation of immunotherapy [ 23 ]. Furthermore, a subset of NSCLC harbors inactivating mutations of both LKB1 and KEAP1/NRF2 and demonstrate a further aggressive clinical course with strong resistance to ICIs treatment [ 72 ]. Papillon-Cavanagh et al analyzed the clinical efficacy of PD1/PD-L1 inhibitors or platinum-based chemotherapy against NSCLC with the double-mutational status in a real world-setting.…”

Section: The Association Between Pd-l1 Expression and Efficacy Of Icis In Nsclc With Driver Gene Alterationsmentioning

confidence: 99%

Current Immunotherapeutic Strategies Targeting the PD-1/PD-L1 Axis in Non-Small Cell Lung Cancer with Oncogenic Driver Mutations

Tanaka

Morise

2021

IJMS

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Treatment strategies targeting programed cell death 1 (PD-1) or its ligand, PD-L1, have been developed as immunotherapy against tumor progression for various cancer types including non-small cell lung cancer (NSCLC). The recent pivotal clinical trials of immune-checkpoint inhibiters (ICIs) combined with cytotoxic chemotherapy have reshaped therapeutic strategies and established various first-line standard treatments. The therapeutic effects of ICIs in these clinical trials were analyzed according to PD-L1 tumor proportion scores or tumor mutational burden; however, these indicators are insufficient to predict the clinical outcome. Consequently, molecular biological approaches, including multi-omics analyses, have addressed other mechanisms of cancer immune escape and have revealed an association of NSCLC containing specific driver mutations with distinct immune phenotypes. NSCLC has been characterized by driver mutation-defined molecular subsets and the effect of driver mutations on the regulatory mechanism of PD-L1 expression on the tumor itself. In this review, we summarize the results of recent clinical trials of ICIs in advanced NSCLC and the association between driver alterations and distinct immune phenotypes. We further discuss the current clinical issues with a future perspective for the role of precision medicine in NSCLC.

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Section: The Association Between Pd-l1 Expression and Efficacy Of Icis In Nsclc With Driver Gene Alterationsmentioning

confidence: 99%

Current Immunotherapeutic Strategies Targeting the PD-1/PD-L1 Axis in Non-Small Cell Lung Cancer with Oncogenic Driver Mutations

Tanaka

Morise

2021

IJMS

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“…For example, in lung cancer, loss of the tumor suppressor STK11 is regarded as driving resistance to both chemotherapy and immunotherapy ( Skoulidis et al, 2018 ). Interestingly, it is the co-occurrence of a RAS mutation that renders these tumors most resistant to ICI-based treatments ( Ricciuti et al, 2021 ). Therefore, given the dominant mutations in pancreatic cancer, it may be challenging to achieve strong immune activation.…”

Section: Genetic Features Of Pdac May Influence Immune Cell Functionmentioning

confidence: 99%

Modulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC

Cattolico

Bailey

Barry

2022

Front. Cell Dev. Biol.

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Immunotherapy has revolutionized the treatment of many cancer types. However, pancreatic ductal adenocarcinomas (PDACs) exhibit poor responses to immune checkpoint inhibitors with immunotherapy-based trials not generating convincing clinical activity. PDAC tumors often have low infiltration of tumor CD8+ T cells and a highly immunosuppressive microenvironment. These features classify PDAC as immunologically “cold.” However, the presence of tumor T cells is a favorable prognostic feature in PDAC. Intrinsic tumor cell properties govern interactions with the immune system. Alterations in tumor DNA such as genomic instability, high tumor mutation burden, and/or defects in DNA damage repair are associated with responses to both immunotherapy and chemotherapy. Cytotoxic or metabolic stress produced by radiation and/or chemotherapy can act as potent immune triggers and prime immune responses. Damage- or stress-mediated activation of nucleic acid-sensing pathways triggers type I interferon (IFN-I) responses that activate innate immune cells and natural killer cells, promote maturation of dendritic cells, and stimulate adaptive immunity. While PDAC exhibits intrinsic features that have the potential to engage immune cells, particularly following chemotherapy, these immune-sensing mechanisms are ineffective. Understanding where defects in innate immune triggers render the PDAC tumor–immune interface less effective, or how T-cell function is suppressed will help develop more effective treatments and harness the immune system for durable outcomes. This review will focus on the pivotal role played by IFN-I in promoting tumor cell–immune cell cross talk in PDAC. We will discuss how PDAC tumor cells bypass IFN-I signaling pathways and explore how these pathways can be co-opted or re-engaged to enhance the therapeutic outcome.

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“…KEAP1 loss-of-function activates the KEAP1-NRF2 axis, leading to dependency on glutaminolysis and promoting KRAS-driven lung adenocarcinomas. 2 Although the association of NRF2 activation and chemoresistance or radiation resistance is quite well established, 3 association with the lack of activity of immune checkpoint inhibition was so far unknown.In this issue of the Journal of Thoracic Oncology, Ricciuti et al 4 provide us with very important data on clinicogenomic associations of patients with lung adenocarcinoma who received immune checkpoint inhibitors. In a total of 1261 subjects, from two independent retrospective institutional cohorts, the authors revealed that STK11 loss (approximately 20% of patients) or KEAP1 loss (approximately 20% of patients) is associated with reduced efficacy of immunotherapy, but only in those patients whose tumors had cooccurring KRAS mutations.…”

mentioning

confidence: 99%

“…In this issue of the Journal of Thoracic Oncology, Ricciuti et al 4 provide us with very important data on clinicogenomic associations of patients with lung adenocarcinoma who received immune checkpoint inhibitors. In a total of 1261 subjects, from two independent retrospective institutional cohorts, the authors revealed that STK11 loss (approximately 20% of patients) or KEAP1 loss (approximately 20% of patients) is associated with reduced efficacy of immunotherapy, but only in those patients whose tumors had cooccurring KRAS mutations.…”

mentioning

confidence: 99%

STK11 and KEAP1 Mutations in Lung Adenocarcinoma: Solving the Puzzle Continues

Dziadziuszko

2022

Journal of Thoracic Oncology

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P14.26 Diminished Efficacy of PD-(L)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma is Impacted by KRAS Mutation Status

Cited by 12 publications

References 0 publications

Current Immunotherapeutic Strategies Targeting the PD-1/PD-L1 Axis in Non-Small Cell Lung Cancer with Oncogenic Driver Mutations

Current Immunotherapeutic Strategies Targeting the PD-1/PD-L1 Axis in Non-Small Cell Lung Cancer with Oncogenic Driver Mutations

Modulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC

STK11 and KEAP1 Mutations in Lung Adenocarcinoma: Solving the Puzzle Continues

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