Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts

Gris-Oliver, Albert; Palafox, Marta; Monserrat, Laia; Brasó-Maristany, Fara; Òdena, Andreu; Sánchez-Guixé, Mònica; Ibrahim, Yasir H.; Villacampa, Guillermo; Grueso, Judit; Parés, Mireia; Guzmán, Marta; Rodríguez, Olga; Bruna, Alejandra; Hirst, Caroline S.; Barnicle, Alan; Bruin, Elza C. de; Reddy, A. Lavakumar; Schiavon, Gaia; Arribas, Joaquı́n; Mills, Gordon B.; Caldas, Carlos; Dienstmann, Rodrigo; Prat, Aleix; Nuciforo, Paolo; Razavi, Pedram; Scaltriti, Maurizio; Turner, Nicholas C.; Saura, Cristina; Davies, Barry R.; Oliveira, Mafalda; Serra, Violeta

doi:10.1158/1078-0432.ccr-19-3324

Cited by 25 publications

(20 citation statements)

References 49 publications

(46 reference statements)

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“…4E). To determine the effects of this suppression, we treated Lepto1 cells with an AKT inhibitor (AZD5363) or an mTOR inhibitor (Rapamycin), both currently in use or under development to target solid tumors46, 47,48,49,50. Treatment with either suppressed Lepto1 cell viability with IC50 values in the nanomolar range (Suppl.…”

Section: Opc-derived Tpp1 Is a Candidate Regulator Of Gm-csf In Her2+mentioning

confidence: 99%

GM-CSF signaling is critical for HER2+ breast leptomeningeal carcinomatosis

Ansari¹,

Bhan²,

Chen³

et al. 2020

Preprint

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Leptomeningeal carcinomatosis (LC), when tumor cells spread to leptomeninges surrounding the brain and spinal cord. HER2+ breast cancer is the most common origin of LC. HER2+ LC remains incurable, with few treatment options and response rates of <20%. One major limitation in development of HER2+ LC therapies has been lack of clinically relevant HER2+ LC primary cell-lines and animal models. To address this, we generated cell lines and patient-derived xenograft models using nodular HER2+ LC. This led to identification of granulocyte-macrophage colony-stimulating factor (GM-CSF) as an oncogenic autocrine driver of HER2+ LC. We observed that oligodendrocyte progenitor cells (OPCs) inhibit growth of HER2+ LC in vitro and in vivo. Furthermore, OPC-derived factor TPP1 degrades GM-CSF, decreasing GM-CSF signaling and suppressing HER2+ LC growth. Lastly, we determined that synergistic inactivation of GM-CSF signaling via the intrathecal delivery neutralizing anti-GM-CSF antibodies and a pan-Aurora kinase inhibitor (CCT137690) antagonizes development of HER2+ LC in vivo.

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Section: Opc-derived Tpp1 Is a Candidate Regulator Of Gm-csf In Her2+mentioning

confidence: 99%

GM-CSF signaling is critical for HER2+ breast leptomeningeal carcinomatosis

Ansari¹,

Bhan²,

Chen³

et al. 2020

Preprint

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“…In closing, therapies for metastatic BC that progress on or after CDK4/6i treatment currently being tested in the clinic include: 1) ET or more potent SERDs in endocrine sensitive patients, albeit this patient population is difficult to identify (NCT02338349, NCT03616587); 2) continuation of CDK4/6i with a different ET backbone (NCT03616587; NCT03809988); 3) continuation of ET with a different CDK4/6i; for example with abemaciclib, because it has additional targets including CDK1/2 complexes 50 ; 4) different ET combined with a PI3Ki in PI3KCA mutant ER + BC 17,36 ; or 5) different ET combined with an AKT inhibitor in PIK3CA/AKT1/PTEN altered tumors (NCT04305496). In this context, our preclinical data previously reported suggest that PTEN alterations alone do not result in benefit to AKT inhibitors 51 . Here, we report that the combination of ribociclib with the PI3K inhibitor alpelisib (or palbociclib with GDC-0032) has remarkable antitumor activity in non-basal like PDXs independent of PIK3CA mutation and this observation is novel 11,52 .…”

Section: Discussionmentioning

confidence: 88%

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Palafox

Monserrat

Bellet³

et al. 2021

Preprint

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Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), combined with endocrine therapy (ET), have demonstrated higher antitumor activity than ET alone for the treatment of advanced estrogen receptor-positive (ER+) breast cancer (BC). Some ER+ BC are de novo resistant to CDK4/6i and others develop acquired resistance. Therapies for tumors after progression are needed. Here, we demonstrate that p16 overexpression is associated with reduced antitumor activity of CDK4/6i in patient-derived xenografts (PDX; n=37) and ER+ BC cell lines, and reduced response of early/advanced ER+HER2- BC patients (n=49) to CDK4/6i. We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome in ER+, CDK4/6i-treated BC PDX and patients. Combination of CDK4/6i ribociclib with PI3K inhibitor (PI3Ki) alpelisib showed antitumor activity in ER+ non-basal-like BC PDX, independently of PIK3CA or RB1 mutation (n=25). Our results offer new insights into predicting primary and acquired resistance to CDK4/6i and post-progression therapeutic strategies.

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“… [ 234 ] Akt1 E17K Breast cancer, ovarian cancer, endometrial carcinoma, meningioma, etc. [ 232 , 240 ] Activating Akt1/2 indels Breast cancer, prostate cancer, clear cell renal cancer, etc. [ 239 ] ARID1A/B mutations or deficiency Gastric, ovarian and endometrioid carcinoma, medulloblastoma [ 245 – 247 ] SF3B1 mutation Myelodysplastic/myeloproliferative neoplasms, melanoma, breast cancer, pancreatic cancer, prostate cancer, AML, etc.…”

Section: Biomarkers and Molecular Basis Of Response To Akt Inhibitors In Cancermentioning

confidence: 99%

“…Another study demonstrates that the presence of PIK3CA / AKT1 mutations and absence of alterations in MTOR or TSC1 were associated with sensitivity to capivasertib monotherapy in HER2 − breast cancer [ 240 ]. The presence of AKT1 E17K and coincident PI3K pathway hotspot mutations may render tumors more responsive to Akt inhibition [ 232 ].…”

Section: Biomarkers and Molecular Basis Of Response To Akt Inhibitors In Cancermentioning

confidence: 99%

Targeting Akt in cancer for precision therapy

et al. 2021

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Biomarkers-guided precision therapeutics has revolutionized the clinical development and administration of molecular-targeted anticancer agents. Tailored precision cancer therapy exhibits better response rate compared to unselective treatment. Protein kinases have critical roles in cell signaling, metabolism, proliferation, survival and migration. Aberrant activation of protein kinases is critical for tumor growth and progression. Hence, protein kinases are key targets for molecular targeted cancer therapy. The serine/threonine kinase Akt is frequently activated in various types of cancer. Activation of Akt promotes tumor progression and drug resistance. Since the first Akt inhibitor was reported in 2000, many Akt inhibitors have been developed and evaluated in either early or late stage of clinical trials, which take advantage of liquid biopsy and genomic or molecular profiling to realize personalized cancer therapy. Two inhibitors, capivasertib and ipatasertib, are being tested in phase III clinical trials for cancer therapy. Here, we highlight recent progress of Akt signaling pathway, review the up-to-date data from clinical studies of Akt inhibitors and discuss the potential biomarkers that may help personalized treatment of cancer with Akt inhibitors. In addition, we also discuss how Akt may confer the vulnerability of cancer cells to some kinds of anticancer agents.

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Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts

Cited by 25 publications

References 49 publications

GM-CSF signaling is critical for HER2+ breast leptomeningeal carcinomatosis

GM-CSF signaling is critical for HER2+ breast leptomeningeal carcinomatosis

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Targeting Akt in cancer for precision therapy

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