Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss

Sep 24, 2026

Uploaded by Rowan

SMARCA4/2-loss in cancers suppresses GLUT1 expression, leading to reduced glucose uptake and glycolysis while increasing reliance on oxidative phosphorylation (OXPHOS). To adapt, SMARCA4/2-deficient cells elevate SLC38A2, enhancing glutamine import to fuel OXPHOS. As a result, these cells and tumors become highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Alanine supplementation, also imported via SLC38A2, competes with glutamine uptake and selectively induces death in SMARCA4/2-deficient cancer. At clinically relevant dosing, alanine synergizes with OXPHOS inhibition or conventional chemotherapy, producing strong antitumor activity in patient-derived xenografts, revealing GLUT1/SLC38A2-mediated metabolic vulnerabilities.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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Introduction

Results

SMARCA4/2-deﬁcient cancer cells have reduced glycolysis and depend on OXPHOS

Article [https://doi.org/10.1038/s41467-023-38594-3](https://doi.org/10.1038/s41467-023-38594-3) Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss Received: 28 March 2023 | Accepted: 9 May 2023 | | --- | | | | Check for updates | Xianbing Zhu1,2,19, Zheng Fu1,2,19, Shary Y. Chen3,4,19, Dionzie Ong3, Giulio Aceto1,2, Rebecca Ho3,4, Jutta Steinberger1,2, Anie Monast1,2, Virginie Pilon1,2, Eunice Li3, Monica Ta3, Kyle Ching3, Bianca N. Adams1,2, Gian L. Negri 5, Luc Choiniere6, Lili Fu7, Kitty Pavlakis8, Patrick Pirrotte 9,10, Daina Z. Avizonis6, Jeffrey Trent 11, Bernard E. Weissman12,13, Ramon I. Klein Geltink 3, Gregg B. Morin 5,14, Morag Park 1,2, David G. Huntsman3,4,15, William D. Foulkes 16,17,18, Yemin Wang 3,4,20 & Sidong Huang 1,2,20 SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deﬁcient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss ofSMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deﬁcient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deﬁcient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deﬁcient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our ﬁndings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers. The SWI/SNF family of ATP-dependent chromatin remodeling complexes regulate transcription by controlling chromatin accessibility1,2. Mutations affecting various SWI/SNF subunits are found in ~25% of all human cancers, highlighting their critical roles in tumorigenesis3. SMARCA4, which encodes one of the two mutually exclusive ATPases of the SWI/SNF complexes, is frequently inactivated by mutations; in contrast, SMARCA2, the paralog of SMARCA4, is rarely mutated but often epigenetically silenced in tumors3,4. Cancer cells deﬁcient in either SMARCA4 or SMARCA2 are vulnerable to genetic ablation of the remaining paralog5–8, a synthetic lethality that is being explored as a potential therapeutic strategy. However, concurrent loss of both SMARCA4 and SMARCA2 (referred to as SMARCA4/2 thereafter) characterizes small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), a rare but lethal ovarian cancer affecting young women A full list of afﬁliations appears at the end of the paper. e-mail: [yewang@bccrc.ca](yewang@bccrc.ca); [sidong.huang@mcgill.ca](sidong.huang@mcgill.ca) without other recurrent genetic alterations9–14 and also occurs in other highly aggressive human malignancies, including non-small cell lung cancers (NSCLCs)15,16, undifferentiated thoracic sarcoma17,18, undifferentiated uterine sarcoma19, and dedifferentiated/undifferentiated carcinoma of various organs20–23. These clinical observations suggest that complete inactivation of SWI/SNF ATPase activity may promote cancer development and/or progression in these contexts. SMARCA4/2-deﬁcient cancers remain difﬁcult to treat as they rarely harbor known druggable mutati

FAQs

What metabolic shift does SMARCA4/2-loss cause in cancer cells?

SMARCA4/2-loss represses GLUT1, reducing glucose uptake and glycolysis. Cells shift toward greater dependence on oxidative phosphorylation (OXPHOS) for energy production.

Why do SMARCA4/2-deficient cells rely on glutamine?

SMARCA4/2-deficient cells increase the amino acid transporter SLC38A2 to import glutamine, using it to fuel OXPHOS when glucose-driven glycolysis is reduced.

How does alanine supplementation selectively kill SMARCA4/2-deficient cancer cells?

Alanine is imported by SLC38A2 and competes with glutamine uptake. This limits glutamine supply and selectively induces death in SMARCA4/2-deficient cancer cells, with synergistic antitumor effects when combined with OXPHOS inhibition or chemotherapy.

Sep 24, 2026

Uploaded by Rowan