Home > Institute Collections > W500 > Anti-PD1 prolongs the response of PI3K and farnesyl transferase inhibition in HRAS- and PIK3CA-mutant head and neck cancers. > print

001     306274
005     20251119102054.0
024 7 _ |a 10.1016/j.neo.2025.101157
|2 doi
024 7 _ |a pmid:40117718
|2 pmid
024 7 _ |a pmc:PMC11978339
|2 pmc
024 7 _ |a 1522-8002
|2 ISSN
024 7 _ |a 1476-5586
|2 ISSN
037 _ _ |a DKFZ-2025-02500
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Manikandan, Dinesh Babu
|b 0
245 _ _ |a Anti-PD1 prolongs the response of PI3K and farnesyl transferase inhibition in HRAS- and PIK3CA-mutant head and neck cancers.
260 _ _ |a Basingstoke
|c 2025
|b Stockton Press
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
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|0 PUB:(DE-HGF)16
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336 7 _ |a ARTICLE
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336 7 _ |a JOURNAL_ARTICLE
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336 7 _ |a Journal Article
|0 0
|2 EndNote
500 _ _ |a #DKFZ-MOST-Ca204#
520 _ _ |a Tipifarnib, 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.
588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 7 |a Alpelisib
|2 Other
650 _ 7 |a Anti-PD1
|2 Other
650 _ 7 |a HRAS
|2 Other
650 _ 7 |a Head and neck cancer
|2 Other
650 _ 7 |a PI3K
|2 Other
650 _ 7 |a Tipifarnib
|2 Other
650 _ 7 |a Class I Phosphatidylinositol 3-Kinases
|0 EC 2.7.1.137
|2 NLM Chemicals
650 _ 7 |a Proto-Oncogene Proteins p21(ras)
|0 EC 3.6.5.2
|2 NLM Chemicals
650 _ 7 |a Farnesyltranstransferase
|0 EC 2.5.1.29
|2 NLM Chemicals
650 _ 7 |a tipifarnib
|0 MAT637500A
|2 NLM Chemicals
650 _ 7 |a Quinolones
|2 NLM Chemicals
650 _ 7 |a Alpelisib
|0 08W5N2C97Q
|2 NLM Chemicals
650 _ 7 |a PIK3CA protein, human
|0 EC 2.7.1.137
|2 NLM Chemicals
650 _ 7 |a Phosphoinositide-3 Kinase Inhibitors
|2 NLM Chemicals
650 _ 7 |a Immune Checkpoint Inhibitors
|2 NLM Chemicals
650 _ 7 |a Pik3ca protein, mouse
|0 EC 2.7.1.137
|2 NLM Chemicals
650 _ 7 |a Programmed Cell Death 1 Receptor
|2 NLM Chemicals
650 _ 7 |a Thiazoles
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Class I Phosphatidylinositol 3-Kinases: genetics
|2 MeSH
650 _ 2 |a Class I Phosphatidylinositol 3-Kinases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Proto-Oncogene Proteins p21(ras): genetics
|2 MeSH
650 _ 2 |a Head and Neck Neoplasms: drug therapy
|2 MeSH
650 _ 2 |a Head and Neck Neoplasms: genetics
|2 MeSH
650 _ 2 |a Head and Neck Neoplasms: pathology
|2 MeSH
650 _ 2 |a Head and Neck Neoplasms: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Farnesyltranstransferase: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Quinolones: pharmacology
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Phosphoinositide-3 Kinase Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Immune Checkpoint Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Xenograft Model Antitumor Assays
|2 MeSH
650 _ 2 |a Programmed Cell Death 1 Receptor: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a CD8-Positive T-Lymphocytes: immunology
|2 MeSH
650 _ 2 |a Signal Transduction: drug effects
|2 MeSH
650 _ 2 |a Thiazoles
|2 MeSH
700 1 _ |a Jagadeeshan, Sankar
|b 1
700 1 _ |a Mathukkada, Sooraj
|b 2
700 1 _ |a Shareb, Raghda Abu
|b 3
700 1 _ |a Prasad, Manu
|b 4
700 1 _ |a Belsamma, Liju Vijaya Steltar
|b 5
700 1 _ |a Marripati, Divyasree
|b 6
700 1 _ |a Erez, Noga
|b 7
700 1 _ |a Wainer, Monica
|b 8
700 1 _ |a Geva, Amit
|b 9
700 1 _ |a Raviv, Danielle
|b 10
700 1 _ |a Allon, Irit
|b 11
700 1 _ |a Morris, Luc Gt
|b 12
700 1 _ |a Su, Gloria H
|b 13
700 1 _ |a Wang, Hai
|b 14
700 1 _ |a Rosenberg, Ari J
|b 15
700 1 _ |a Kessler, Linda
|b 16
700 1 _ |a Burrows, Francis
|b 17
700 1 _ |a Elkabets, Moshe
|b 18
773 _ _ |a 10.1016/j.neo.2025.101157
|g Vol. 63, p. 101157 -
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