Targeting DDR2 enhances tumor response to anti–PD-1 immunotherapy

Tu, Megan M.; Lee, Francis Y. F.; Jones, Robert T.; Kimball, Abigail K.; Saravia, Elizabeth; Graziano, Robert F.; Coleman, Brianne; Menard, Krista; Yan, Jun; Michaud, Erin; Han, Chang; Abdel-Hafiz, Hany A.; Rozhok, Andrii I.; Duex, Jason E.; Agarwal, Neeraj; Chauca-Diaz, Ana; Johnson, Linda K.; Ng, Terry L.; Cambier, John C.; Clambey, Eric T.; Costello, James C.; Korman, Alan J.; Theodorescu, Dan

doi:10.1126/sciadv.aav2437

Cited by 99 publications

(102 citation statements)

References 54 publications

(84 reference statements)

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“…Downregulation of DDR2 in A375 human melanoma cells reduced experimental liver metastases in mice (Badiola, Villacé, Basaldua, & Olaso, 2011). In contrast, a recent study showed no effect of DDR2 downregulation on the ability of mouse B16-F10 melanoma cells to colonize lungs in experimental metastasis assays (Tu et al, 2019). However, a previous study demonstrated that inoculation of B16-F10 melanoma cells into DDR2-deficient mice decreased subcutaneous tumor growth and experimental metastases, suggesting that stromal DDR2 plays a role in melanoma malignancy (Zhang et al, 2014).…”

Section: Introductionmentioning

confidence: 97%

Discoidin domain receptors: A promising target in melanoma

Moura

Battistella

Sohail

et al. 2019

Pigment Cell Melanoma Res

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The discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1‐IN‐1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma.

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Section: Introductionmentioning

confidence: 97%

Discoidin domain receptors: A promising target in melanoma

Moura

Battistella

Sohail

et al. 2019

Pigment Cell Melanoma Res

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“…Alterations of some top genes in our prediction, such as B2M, JAK1, JAK2, HSP90 , and IFNG , are known to be associated with poor response to anti-PD-1 therapy [7, 33-36]. Several genes that were recently found to be associated with anti-PD-1 response were also identified in the top list of our prediciton, such as KRAS [37], STK11 [38], DDR2 [39], and ATR [40].…”

Section: Resultsmentioning

confidence: 99%

“…Recently, several efforts tested possible drug combinations with checkpoint inhibitors. However, tests of all the possible drug combinations with PD-1/PD-L1 inhibitors may exceed the number of eligible cancer patients who can be enrolled in clinical trials, and are therefore not feasible in the context of clinical trials [39]. With the incorporation of drug target information, our approach can be used to effectively identify compounds that may have action in pathways that enhance response to anti-PD-1 therapy.…”

Section: Discussionmentioning

confidence: 99%

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

Wang

Livingston

et al. 2020

Preprint

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24 Background: Despite remarkable success, only a subset of cancer patients have shown benefit from the anti-PD1 25 therapy. Therefore, there is a growing need to identify predictive biomarkers and therapeutic combinations for 26 improving the clinical efficacy. 27Results: Based upon the hypothesis that aberrations of any gene that are close to MHC class I genes in the gene 28 network are likely to deregulate MHC I pathway and affect tumor response to anti-PD1, we developed a network 29 approach to infer genes, pathway, and potential therapeutic target genes associated with response to PD-1/PD-L1 30 checkpoint immunotherapies in cancer. Our approach successfully identified genes (e.g. B2M and PTEN) and 31 pathways (e.g. JAK/STAT and WNT) known to be associated with anti-PD1 response. Our prediction was further 32 validated by 5 CRISPR gene sets associated with tumor resistance to cytotoxic T cells. Our results also showed that 33 many cancer genes that act as hubs in the gene network may drive immune evasion through indirectly deregulating 34 the MHC I pathway. The integration analysis of transcriptomic data of the 34 TCGA cancer types and our prediction 35 reveals that MHC I-immunoregulations may be tissue-specific. The signature-based score, the MHC I association 36 immunoscore (MIAS), calculated by integration of our prediction and TCGA melanoma transcriptomic data also 37 showed a good correlation with patient response to anti-PD1 for 354 melanoma samples complied from 5 cohorts. 38In addition, most targets of the 36 compounds that have been tested in clinical trials or used for combination 39 treatments with anti-PD1 are in the top list of our prediction (AUC=0.833). Integration of drug target data with our 40 top prediction further identified compounds that were recently shown to enhance tumor response to anti-PD1, such 41 as inhibitors of GSK3B, CDK, and PTK2. 42Conclusion: Our approach is effective to identify candidate genes and pathways associated with response to anti- 43PD-1 therapy, and can also be employed for in silico screening of potential compounds to enhances the efficacy of 44 anti-PD1 agents against cancer. 45 46 47 48 50 Breakthroughs in cancer immunotherapies have opened a new front in the war against cancer [1]. Instead of 51 directly targeting cancer cells using specific inhibitors, immunotherapies stimulate and modulate the host's 52 immune system to eliminate cancer cells. Recently, immune checkpoint blockade (ICB), which enhances T-cell 53 activity by inhibiting immunosuppressive checkpoint molecules such as cytotoxic T-lymphocyte-associated antigen 54 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1), has produced 55remarkably durable responses in some cancer patients. Despite these successes, only a subset of cancer patients 56 benefits from these therapies, and rates of response vary widely among cancer types. Therefore, there is a growing 57 need to understand the mechanisms underlying this de novo resistance, to select predictive biomar...

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“…Lizotte et al developed an in vitro luciferase-based screening assay to identify small molecules, which modulate T-cell-mediated killing of tumor cells and validated epidermal growth factor receptor (EGFR) inhibitors at potentiators of anti-PD-1 immunotherapy [193]. Tu et al utilized in vivo functional genomics to identify discoidin domain receptor 2 (DDR2) as a target mechanism to sensitize multiple tumor types to anti-PD-1 treatment [194]. In more encompassing studies, genome-wide CRISPR-Cas9 screens have been leveraged to further elucidate genes, which permit tumor cell escape from immunosurveillance.…”

Section: High-throughput Methods Of Discovering Combinational Therapiesmentioning

confidence: 99%

Determinants of Resistance to Checkpoint Inhibitors

Tran

Theodorescu

2020

IJMS

Self Cite

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The development of immune checkpoint inhibitors (ICIs) has drastically altered the landscape of cancer treatment. Since approval of the first ICI for the treatment of advanced melanoma in 2011, several therapeutic agents have been Food and Drug Administration (FDA)-approved for multiple cancers, and hundreds of clinical trials are currently ongoing. These antibodies disrupt T-cell inhibitory pathways established by tumor cells and thus re-activate the host’s antitumor immune response. While successful in many cancers, several types remain relatively refractory to treatment or patients develop early recurrence. Hence, there is a great need to further elucidate mechanisms of resistant disease and determine novel, effective, and tolerable combination therapies to enhance efficacy of ICIs.

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Targeting DDR2 enhances tumor response to anti–PD-1 immunotherapy

Abstract: In vivo–based functional genomic screen identifies DDR2 as an important determinant of efficacy of anti–PD-1 immunotherapy.

Cited by 99 publications

References 54 publications

Discoidin domain receptors: A promising target in melanoma

Discoidin domain receptors: A promising target in melanoma

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

Determinants of Resistance to Checkpoint Inhibitors

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