000306274 001__ 306274
000306274 005__ 20251119102054.0
000306274 0247_ $$2doi$$a10.1016/j.neo.2025.101157
000306274 0247_ $$2pmid$$apmid:40117718
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000306274 0247_ $$2ISSN$$a1476-5586
000306274 037__ $$aDKFZ-2025-02500
000306274 041__ $$aEnglish
000306274 082__ $$a610
000306274 1001_ $$aManikandan, Dinesh Babu$$b0
000306274 245__ $$aAnti-PD1 prolongs the response of PI3K and farnesyl transferase inhibition in HRAS- and PIK3CA-mutant head and neck cancers.
000306274 260__ $$aBasingstoke$$bStockton Press$$c2025
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000306274 520__ $$aTipifarnib, a farnesyl transferase inhibitor, has shown promising response in the treatment of HRAS-mutant HNSCC in the clinic, and in combination with a PI3K inhibitor in PIK3CA-mutant mouse models; however, the involvement of antitumor immunity in the efficacy of tipifarnib has not yet been investigated. This study aimed to evaluate the involvement of antitumor immunity in the efficacy of tipifarnib in HRAS- or PIK3CA-mutant HPV-positive and HPV-negative head and neck cancer murine models.To investigate the role of antitumor immunity, we compared the efficacy of tipifarnib in immune-intact C57BL/6 mice and immunodeficient NSG mice. Histopathological analyses were conducted to evaluate PD-L1 expression and the activation of key signaling pathways. Additionally, the synergistic potential of tipifarnib with the PI3Kα inhibitor alpelisib (BYL719) was assessed in vitro and in vivo. Immunohistochemical analysis was performed to examine the infiltration of CD8+T cells, and anti-PD1 treatment was tested to evaluate its potential to prolong progression-free survival.In the HPV-positive HRAS-mutant HNSCC model, the antitumor efficacy of tipifarnib was primarily dependent on CD8+T cell activity, whereas in HPV-negative cancers, the contribution of antitumor immunity was less pronounced. Tipifarnib treatment upregulated PD-L1 expression, potentially inhibiting T cell antitumor activity and inducing hyperactivation of the AKT pathway, which mitigated MAPK inhibition and promoted cell proliferation. Blocking the PI3K pathway with alpelisib demonstrated synergistic antitumor effects in all models. The combination of tipifarnib and alpelisib exhibited greater efficacy in immune-intact mice than in immunodeficient mice, and was accompanied by increased CD8+T cell infiltration. Adding anti-PD1 treatment to the tipifarnib/alpelisib combination further prolonged progression-free survival in tumor-bearing mice.These findings underscore the critical role of antitumor immunity, particularly CD8+T cell activity, in the efficacy of tipifarnib alone and in combination with alpelisib. The triple combination of tipifarnib, alpelisib, and anti-PD1 treatment showed superior antitumor activity and extended survival in preclinical models, suggesting its potential as a therapeutic strategy for HNSCC patients with HRAS- and PIK3CA-mutation.
000306274 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000306274 650_7 $$2Other$$aAlpelisib
000306274 650_7 $$2Other$$aAnti-PD1
000306274 650_7 $$2Other$$aHRAS
000306274 650_7 $$2Other$$aHead and neck cancer
000306274 650_7 $$2Other$$aPI3K
000306274 650_7 $$2Other$$aTipifarnib
000306274 650_7 $$0EC 2.7.1.137$$2NLM Chemicals$$aClass I Phosphatidylinositol 3-Kinases
000306274 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aProto-Oncogene Proteins p21(ras)
000306274 650_7 $$0EC 2.5.1.29$$2NLM Chemicals$$aFarnesyltranstransferase
000306274 650_7 $$0MAT637500A$$2NLM Chemicals$$atipifarnib
000306274 650_7 $$2NLM Chemicals$$aQuinolones
000306274 650_7 $$008W5N2C97Q$$2NLM Chemicals$$aAlpelisib
000306274 650_7 $$0EC 2.7.1.137$$2NLM Chemicals$$aPIK3CA protein, human
000306274 650_7 $$2NLM Chemicals$$aPhosphoinositide-3 Kinase Inhibitors
000306274 650_7 $$2NLM Chemicals$$aImmune Checkpoint Inhibitors
000306274 650_7 $$0EC 2.7.1.137$$2NLM Chemicals$$aPik3ca protein, mouse
000306274 650_7 $$2NLM Chemicals$$aProgrammed Cell Death 1 Receptor
000306274 650_7 $$2NLM Chemicals$$aThiazoles
000306274 650_2 $$2MeSH$$aAnimals
000306274 650_2 $$2MeSH$$aMice
000306274 650_2 $$2MeSH$$aClass I Phosphatidylinositol 3-Kinases: genetics
000306274 650_2 $$2MeSH$$aClass I Phosphatidylinositol 3-Kinases: antagonists & inhibitors
000306274 650_2 $$2MeSH$$aProto-Oncogene Proteins p21(ras): genetics
000306274 650_2 $$2MeSH$$aHead and Neck Neoplasms: drug therapy
000306274 650_2 $$2MeSH$$aHead and Neck Neoplasms: genetics
000306274 650_2 $$2MeSH$$aHead and Neck Neoplasms: pathology
000306274 650_2 $$2MeSH$$aHead and Neck Neoplasms: metabolism
000306274 650_2 $$2MeSH$$aHumans
000306274 650_2 $$2MeSH$$aMutation
000306274 650_2 $$2MeSH$$aFarnesyltranstransferase: antagonists & inhibitors
000306274 650_2 $$2MeSH$$aQuinolones: pharmacology
000306274 650_2 $$2MeSH$$aCell Line, Tumor
000306274 650_2 $$2MeSH$$aDisease Models, Animal
000306274 650_2 $$2MeSH$$aPhosphoinositide-3 Kinase Inhibitors: pharmacology
000306274 650_2 $$2MeSH$$aImmune Checkpoint Inhibitors: pharmacology
000306274 650_2 $$2MeSH$$aXenograft Model Antitumor Assays
000306274 650_2 $$2MeSH$$aProgrammed Cell Death 1 Receptor: antagonists & inhibitors
000306274 650_2 $$2MeSH$$aFemale
000306274 650_2 $$2MeSH$$aCD8-Positive T-Lymphocytes: immunology
000306274 650_2 $$2MeSH$$aSignal Transduction: drug effects
000306274 650_2 $$2MeSH$$aThiazoles
000306274 7001_ $$aJagadeeshan, Sankar$$b1
000306274 7001_ $$aMathukkada, Sooraj$$b2
000306274 7001_ $$aShareb, Raghda Abu$$b3
000306274 7001_ $$aPrasad, Manu$$b4
000306274 7001_ $$aBelsamma, Liju Vijaya Steltar$$b5
000306274 7001_ $$aMarripati, Divyasree$$b6
000306274 7001_ $$aErez, Noga$$b7
000306274 7001_ $$aWainer, Monica$$b8
000306274 7001_ $$aGeva, Amit$$b9
000306274 7001_ $$aRaviv, Danielle$$b10
000306274 7001_ $$aAllon, Irit$$b11
000306274 7001_ $$aMorris, Luc Gt$$b12
000306274 7001_ $$aSu, Gloria H$$b13
000306274 7001_ $$aWang, Hai$$b14
000306274 7001_ $$aRosenberg, Ari J$$b15
000306274 7001_ $$aKessler, Linda$$b16
000306274 7001_ $$aBurrows, Francis$$b17
000306274 7001_ $$aElkabets, Moshe$$b18
000306274 773__ $$0PERI:(DE-600)2008231-9$$a10.1016/j.neo.2025.101157$$gVol. 63, p. 101157 -$$p101157$$tNeoplasia$$v63$$x1522-8002$$y2025
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