Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy

Badarni, Mai; Prasad, Manu; Balaban, Noa; Zorea, Jonathan; Yegodayev, Ksenia M.; Joshua, Ben‐Zion; Dinur, Anat Bahat; Grénman, Reidar; Rotblat, Barak; Cohen, Limor; Elkabets, Moshe

doi:10.1172/jci.insight.125341

Cited by 47 publications

(44 citation statements)

References 64 publications

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“…STC2 increased c‐Jun expression and phosphorylation, and c‐Jun enhanced the transcription of AXL . Consistent with our findings, a recent study showed that c‐Jun expression correlated with AXL expression in PI3K TKI‐resistant cancer cells . The c‐Jun/c‐Fos transcriptional complex increased AXL expression, whereas inhibition of c‐Jun downregulated AXL mRNA and protein expression .…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with our findings, a recent study showed that c‐Jun expression correlated with AXL expression in PI3K TKI‐resistant cancer cells . The c‐Jun/c‐Fos transcriptional complex increased AXL expression, whereas inhibition of c‐Jun downregulated AXL mRNA and protein expression . AXL and EGFR share downstream signaling pathways including the PI3K/Akt and MAPK/ERK .…”

Section: Discussionsupporting

confidence: 92%

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Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer

Liu

Tsai

et al. 2019

Intl Journal of Cancer

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Constitutive activation of the epidermal growth factor receptor (EGFR) signaling pathway is implicated in the initiation and progression of lung cancer. EGFR tyrosine kinase inhibitor (TKI)-targeted therapy has become the standard treatment for nonsmall cell lung cancer (NSCLC) patients. However, acquired resistance to these agents remains a major obstacle for managing NSCLC. Here, we investigated a novel strategy to overcome EGFR TKI resistance by targeting the stanniocalcin 2 (STC2)-JUN-AXL pathway. We revealed that STC2 was expressed at significantly higher levels in EGFR TKI-resistant cells. Further, clinical analysis showed that STC2 expression was increased after the development of EGFR TKI resistance and that higher levels were correlated with shorter progression-free survival in EGFR TKI-treated lung cancer patients. Moreover, STC2 overexpression in EGFR TKI-sensitive cells resulted in EGFR TKI resistance. Conversely, genetic silencing of STC2 rendered EGFR TKI-resistant cells more sensitive to EGFR TKIs. Mechanically, STC2 enhanced AXL promoter activity by increasing the phosphorylation of c-Jun, which is an indispensable transcription factor that transactivates AXL. STC2 promoted activation of the JUN-AXL-extracellular signal-regulated kinase (ERK) signaling axis in lung cancer cells. Pharmacological or genetic inhibition of AXL-ERK activity inhibited STC2-mediated EGFR TKI resistance. We also demonstrated that PE2988 cells, a C797Sindependent osimertinib-resistant primary cancer cell line from a lung cancer patient, responded to combined AXL inhibitor and osimertinib treatment. In conclusion, our research indicates that STC2 overexpression is important for acquired resistance to EGFR TKIs and that STC2-JUN-AXL-ERK signaling might be a potential therapeutic target to overcome resistance to EGFR TKIs.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer

Liu

Tsai

et al. 2019

Intl Journal of Cancer

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“…Genomic aberrations in AXL are relatively rare in cancers. It appears that AXL is primarily regulated at the levels of the promoter [42][43][44] and protein stability 12,[45][46][47] . In this study, we showed that p85β but not p85α regulated the autophagylysosomal machinery to promote AXL protein stabilization and downstream signaling (Fig.…”

Section: Discussionmentioning

confidence: 99%

p85β regulates autophagic degradation of AXL to activate oncogenic signaling

et al. 2020

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PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85β are poorly understood. Here we report that p85β upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85β activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85β alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85β, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85β expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85β-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.

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“…The rationale for combining pathways inhibitors to prevent PI3Ki resistance has been shown to achieve extended response in pre-clinical HNSCC models. For example, by simultaneously blocking mTORC2 [ 30 , 31 ], human epidermal growth factor receptor 3 (HER3) [ 32 , 33 ], Epidermal growth factor receptor (EGFR) [ 34 , 35 ], Jun N-terminal kinases (JNK) [ 36 ], Extracellular signal-regulated kinases (ERK) [ 37 ], and AXL [ 22 ]. Previously, Vora et al [ 23 ] and others [ 26 ] described in both pre-clinical breast cancer models and in patients, that resistance to BYL719 is mediated by sustained activation of mTORC1 that regulates the CDK 4/6–Rb axis.…”

Section: Discussionmentioning

confidence: 99%

CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma

Remer

Badarni

Hikri

et al. 2020

JCM

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Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients.

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Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy

Cited by 47 publications

References 64 publications

Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer

Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer

p85β regulates autophagic degradation of AXL to activate oncogenic signaling

CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma

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