ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumor cell survival

Alam, Sk Kayum; Wang, Li; Ren, Yanan; Hernandez, Christina E.; Kosari, Farhad; Roden, Anja C.; Yang, Rendong; Hoeppner, Luke H.

doi:10.1101/703975

Cited by 3 publications

(2 citation statements)

References 75 publications

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“…It is currently unknown whether most identified upstream and downstream signalling molecules interact with DARPP-32 isoforms directly or indirectly. 29 These future opportunities, the collective prior studies reporting the role of DARPP-32 and t-DARPP in oncogenesis and resistance to therapy, and our findings that upregulation of DARPP-32 isoforms in human SCLC promote growth, anti-apoptotic mechanisms and pro-survival signalling in lung tumour cells of neuroendocrine origin underscore the promise of pursuing DARPP-32 and t-DARPP as potential therapeutic targets or prognostic indicators 81 .…”

Section: Discussionmentioning

confidence: 76%

ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation

et al. 2020

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BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, and new molecular insights are necessary for prognostic and therapeutic advances. METHODS: Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) and its N-terminally truncated splice variant, t-DARPP, were stably overexpressed or ablated in human DMS-53 and H1048 SCLC cells. Functional assays and immunoblotting were used to assess how DARPP-32 isoforms regulate SCLC cell growth, proliferation, and apoptosis. DARPP-32-modulated SCLC cells were orthotopically injected into the lungs of SCID mice to evaluate how DARPP-32 and t-DARPP regulate neuroendocrine tumour growth. Immunostaining for DARPP-32 proteins was performed in SCLC patient-derived specimens. Bioinformatics analysis and subsequent transcription assays were used to determine the mechanistic basis of DARPP-32-regulated SCLC growth. RESULTS: We demonstrate in mice that DARPP-32 and t-DARPP promote SCLC growth through increased Akt/Erk-mediated proliferation and anti-apoptotic signalling. DARPP-32 isoforms are overexpressed in SCLC patient-derived tumour tissue, but undetectable in physiologically normal lung. Achaete-scute homologue 1 (ASCL1) transcriptionally activates DARPP-32 isoforms in human SCLC cells. CONCLUSIONS: We reveal new regulatory mechanisms of SCLC oncogenesis that suggest DARPP-32 isoforms may represent a negative prognostic indicator for SCLC and serve as a potential target for the development of new therapies.

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Section: Discussionmentioning

confidence: 76%

ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation

et al. 2020

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“…Two days post-transfection, the lentivirus collected from the cell culture media was concentrated using Retro-X concentrator (Takara). The concentrated lentivirus was used immediately to transduce human NSCLC cell lines, HCC827P and HCC827GR, as described previously 46 . Luciferase-labeled stable human NSCLC cells were obtained following 72h of hygromycin (Sigma) selection after transduction.…”

Section: Introductionmentioning

confidence: 99%

DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma

Alam

Zhang

Wang

et al. 2021

Preprint

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While molecular targeted therapies have improved prognoses of advanced stage lung adenocarcinoma expressing oncogenic driver mutations, acquired therapeutic resistance continues to be a major problem. Epidermal growth factor receptor (EGFR) activating mutations are among the most common targetable genetic alterations in lung adenocarcinoma, and EGFR tyrosine kinase inhibitors (TKIs) are recommended first-line therapy for EGFR mutation positive cancer patients. Unfortunately, most patients develop resistance to EGFR TKIs and rapid disease progression occurs. A better mechanistic understanding of therapy refractory cancer progression is necessary to develop new therapeutic approaches to predict and prevent acquired resistance to EGFR TKIs. Here, we identify a new mechanism of ERBB3-mediated resistance to EGFR TKIs in human lung adenocarcinoma. Specifically, we show that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32) physically recruits ERBB3 to EGFR to mediate a switch from EGFR homodimers to EGFR:ERBB3 heterodimers to bypass EGFR TKI-mediated inhibition to potentiate ERBB3-dependent activation of oncogenic AKT and ERK signaling that drives therapy refractory tumor cell survival. In a cohort of paired tumor specimens derived from 30 lung adenocarcinoma patients before and after the development of EGFR TKI refractory disease progression, we reveal that DARPP-32 as well as kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired EGFR TKI resistance. In vivo studies suggest that ablation of DARPP-32 protein activity sensitizes gefitinib-resistant lung tumor xenografts to EGFR TKI treatment, while DARPP-32 overexpression increases gefitinib-refractory lung cancer progression in gefitinib-sensitive lung tumors orthotopically xenografted into mice. Taken together, our findings introduce a DARPP-32-mediated, ERBB3-dependent mechanism used by lung tumor cells to evade EGFR TKI-induced cell death, potentially paving the way for the development of new therapies to prevent or overcome therapy-refractory lung adenocarcinoma progression.

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IKKα promotes lung adenocarcinoma growth through activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity

Alam

Wang

Zhu

et al. 2022

Preprint

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Non-small cell lung cancer (NSCLC) accounts for 80-85% cases of lung cancer cases. Diagnosis at advanced stages is common, after which therapy-refractory disease progression frequently occurs. Therefore, a better understanding of the molecular mechanisms that control NSCLC progression is necessary to develop new therapies. Overexpression of IκB kinase α (IKKα) in NSCLC correlates with poor patient survival. IKKα is an NF-κB-activating kinase that is important in cell survival and differentiation, but its regulation of oncogenic signaling is not well understood. We recently demonstrated that IKKα promotes NSCLC cell migration by physically interacting with dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated splice variant, t-DARPP. Here, we show that IKKα phosphorylates DARPP-32 at threonine 34, resulting in DARPP-32-mediated inhibition of protein phosphatase 1 (PP1), subsequent PP1-mediated dephosphorylation of ERK, and activation of ERK signaling to promote lung oncogenesis. Correspondingly, DARPP-32 ablation in human lung adenocarcinoma cells reduced their anchorage-independent growth in soft agar. Mice challenged with IKKα-ablated HCC827 cells exhibited less lung tumor growth than mice orthotopically administered control HCC827 cells. Our findings suggest that IKKα drives NSCLC growth through activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity.

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ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumor cell survival

Cited by 3 publications

References 75 publications

ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation

ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation

DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma

IKKα promotes lung adenocarcinoma growth through activation of ERK signaling via DARPP-32-mediated inhibition of PP1 activity

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