Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-04-16 DOI:10.1016/j.bbadis.2025.167859

Wenying Shan , Shao-Lin Zhang , Yehuda G. Assaraf , Kin Yip Tam

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Abstract

KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation in vitro, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.

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混合代谢状态携带KRAS Q61H突变的非小细胞肺癌患者，联合抑制己糖激酶2和丙酮酸脱氢酶可克服SHP2抑制剂耐药性

KRAS Q61H是一种侵袭性的致癌驱动突变，使癌细胞对SHP2抑制剂（SHP2i）具有耐药性。一些转移性和化疗耐药的非小细胞肺癌（NSCLC）细胞表现出糖酵解和氧化磷酸化（OXPHOS）共存的混合代谢状态。因此，我们评估了己糖激酶2 （HK2）和丙酮酸脱氢酶（PDH）抑制剂benserazide （Benz）和CPI-613联合使用对携带KRAS Q61H驱动突变的NSCLC NCI-H460细胞的体外和体内疗效。该组合协同破坏杂交代谢状态，抑制NCI-H460细胞体外增殖，并显著抑制NCI-H460细胞异种移植模型小鼠肿瘤生长。这种抗肿瘤活性的分子基础显然是由于抑制SHP2/SOS1/RAS/MAPK信号通路，导致细胞凋亡增强。此外，该药物组合恢复了对SHP2i的敏感性。同样，在NCI-H460细胞中，SHP2过表达使该药物组合的抗肿瘤活性消失。这些发现表明，奔驰与CPI-613联合靶向KRAS Q61H突变型NSCLC肿瘤的代谢易损性。这些结果为可能治疗显示混合代谢状态的癌细胞提供了一种联合治疗策略，从而克服了化疗耐药性。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.