HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma

Meister, Kara D; Godse, Neal R.; Khan, Nayel; Hedberg, Matthew L.; Kemp, Carolyn; Kulkarni, S. B.; Alvarado, Diego; LaVallee, Theresa; Kim, Seungwon; Grandis, Jennifer R.; Duvvuri, Umamaheswar

doi:10.1038/s41598-019-45589-y

Cited by 15 publications

(12 citation statements)

References 38 publications

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“…In the preclinical study of HNSCC, alpelisib was shown to overcome cetuximab resistance in HNSCC ( 25 ). In addition, alpelisib treatment reduced Akt activation and suppressed tumor growth in HNSCC, in vitro and in vivo ( 25 , 26 ). In the present study the HSC-3 OSCC cell line were found to be sensitive to the anti-proliferative effects of alpelisib.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

et al. 2020

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High expression of the 110 kDa catalytic subunit of the class IA PI3K (PI3Kp110α) may play an important role in cetuximab resistance exhibited by both colorectal cancer and head and neck squamous cell carcinoma. Therefore, the present study aimed to examine the association between the expression of proteins in the PI3Kp110α pathway and cetuximab resistance, and the antitumor effects of alpelisib (PI3K inhibitor) and cetuximab in oral squamous cell carcinoma (OSCC) cells. The association between PI3Kp110α protein expression levels and the tumor response to cetuximab was determined using immunohistochemistry. OSCC cells were treated with alpelisib, cetuximab, or in combination, and the effects were examined in vitro and in vivo. PI3Kp110α protein expression was significantly associated with the tumor response to cetuximab (P<0.05) and 1-year progression-free survival and overall survival (P<0.05). Combined treatment of alpelisib and cetuximab resulted in enhanced antitumor effects in vitro compared with either agent administered alone. In particular, the expression level of N-cadherin, an epithelial-mesenchymal transition-related protein, was decreased, suggesting that the invasion potential of cetuximab-resistant cells decreased. Furthermore, the expression of proteins in the PI3K pathway were decreased in tumors from mice with OSCC xenografts treated with alpelisib and cetuximab in combination. These results indicate that novel regimens of systemic therapy (such as chemotherapy), with combinations of cetuximab and alpelisib, may be beneficial for patients with cetuximab-resistant OSCC.

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Section: Discussionmentioning

confidence: 99%

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

et al. 2020

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“…In summary, our findings highlight the likelihood that the factors governing the acquisition of resistance in HNC HPV+ may be distinct from those in HNC HPV− . While, in HNC HPV− , expression of RTKs increases following PI3K treatment [ 20 , 58 , 59 , 60 , 61 ], in HNC HPV+ , tumor cells acquire resistance to isiPI3K by the secretion of IGF2 to activate IGF1R. Our results provide the first evidence that blocking the IGF2/IGF1R pathway in combination with isiPI3K is a promising therapeutic strategy for treating HNC HPV+ patients.…”

Section: Discussionmentioning

confidence: 79%

“…Different molecular paths can lead to isiPI3K resistance, including sustained activation of mTORC1 [ 21 , 54 , 55 ], PDK1/SGK1 [ 56 ], and MYC [ 57 ]. In HNC HPV− , acquisition of resistance to isiPI3K is driven by increased activity of receptor tyrosine kinases (RTK), like EGFR [ 20 , 58 ], AXL [ 20 , 59 , 60 ], and HER3 [ 61 ], which signal through AKT or RAS/ERK pathways, or by activation of RTKs downstream of ERK/TSC2 [ 61 ], p85 [ 62 ], and CDK4/6 [ 63 ]. While, in HNC HPV− , different mechanisms of resistance to isiPI3K have been well documented by us and by others, in HNC HPV+ , only innate resistance to isiPI3K has been reported [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

Badarni

Prasad

Golden

et al. 2021

Cancers

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Over 50% of human papilloma positive head-and-neck cancer (HNCHPV+) patients harbor genomic-alterations in PIK3CA, leading to hyperactivation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway. Nevertheless, despite PI3K pathway activation in HNCHPV+ tumors, the anti-tumor activities of PI3K pathway inhibitors are moderate, mostly due to the emergence of resistance. Thus, for potent and long-term tumor management, drugs blocking resistance mechanisms should be combined with PI3K inhibitors. Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNCHPV+ cell lines. By comparing the transcriptional landscape of isiPI3K-sensitive tumor cells with that of their corresponding isiPI3K-acquired-resistant tumor cells, we found upregulation of insulin growth factor 2 (IGF2) in the resistant cells. Mechanistically, we show that upon isiPI3K treatment, isiPI3K-sensitive tumor cells upregulate the expression of IGF2 to induce cell proliferation via the activation of the IGF1 receptor (IGF1R). Stimulating tumor cells with recombinant IGF2 limited isiPI3K efficacy and released treated cells from S phase arrest. Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNCHPV+ UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNCHPV+.

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“…Following 24 h of treatment with alpelisib, we observed a significant reduction in the proportion of proliferating (S-phase) cells (Fig. 1 b) [ 24 , 25 ]. To determine whether alpelisib was also able to induce cell death through apoptosis, we examined PARP cleavage (Fig.…”

Section: Resultsmentioning

confidence: 99%

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma

Ruicci

Meens

Plantinga

et al. 2020

J Exp Clin Cancer Res

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Background Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs). Methods Five unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance. Results Prolonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20–35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib. Conclusions We have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients.

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HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma

Cited by 15 publications

References 38 publications

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma

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