CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer

Xing, Fei; Gao, Hongli; Chen, Guanglei; Sun, Lisha; Sun, Jiayi; Qiao, Xinbo; Xue, Jinqi; Liu, Caigang

doi:10.1186/s12943-023-01716-y

Cited by 26 publications

(10 citation statements)

References 37 publications

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“…Our results suggest that CMTM6 is a novel interacting molecule of CD40. Recent studies have identified CMTM6 as a molecule that interacts with numerous transmembrane proteins, including PD-L1, CD58, and HER2 [16][17][18][19]35 . CMTM6 regulates the membrane levels of these proteins in the post-translational modification pathway, impacting tumor growth and tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

CMTM6 maintains B cell-intrinsic CD40 expression to regulate anti-tumor immunity

Long,

Chen,

Chang

et al. 2024

Preprint

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Tumor cell CMTM6 is a novel tumor immunoregulator involved in maintaining membrane levels of several important molecules, such as PD-L1 and CD58. Host CMTM6 may also play a function in the tumor microenvironment. Here, we found that CMTM6 was highly expressed in splenic B cells and tumor-infiltrating B cells. CMTM6 deficiency resulted in impaired splenic development, germinal center B cell differentiation, memory B cell differentiation, and B cell anti-tumor immune responses. Through multi-omics data mining and B-cell agonist screening, we identified that CMTM6 interacted with CD40 and maintained CD40 membrane levels in B cells. CMTM6 regulated CD40 at the post-translational modification stage but not at the transcriptional stage. CMTM6 deficiency led to impaired CD40 signaling-mediated B cell activation, survival, proliferation, and differentiation. In vivo, CMTM6 deficiency leads to a significant decrease in the anti-tumor activity of B cell-dependent CD40 agonists. Collectively, B-cell intrinsic CMTM6 maintains B cell CD40 levels and signaling to promote B cell function and anti-tumor immunity.

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Section: Discussionmentioning

confidence: 99%

CMTM6 maintains B cell-intrinsic CD40 expression to regulate anti-tumor immunity

Long,

Chen,

Chang

et al. 2024

Preprint

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“…The intrinsic mechanism behind this phenomenon is the stabilization of HER2 protein by CMTM6, which inhibits HER2 ubiquitination. HER2 ubiquitination is a process that promotes HER2 degradation [63,64]. Additionally, CMTM6 is a critical regulator of PD-L1 stability in a broad range of cancer cells, and dual inhibition of HER2 and PD-L1 successfully enhances the anti-tumor effect of anti-HER2 monotherapy in HER2-positive tumor cell [65].…”

Section: The "Input Part" Of the Erbb Network Is A Point To Resolve T...mentioning

confidence: 99%

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer

Liu

et al. 2023

Cancers

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The amplification of epidermal growth factor receptor 2 (HER2) is associated with a poor prognosis and HER2 gene is overexpressed in approximately 15–30% of breast cancers. In HER2-positive breast cancer patients, HER2-targeted therapies improved clinical outcomes and survival rates. However, drug resistance to anti-HER2 drugs is almost unavoidable, leaving some patients with an unmet need for better prognoses. Therefore, exploring strategies to delay or revert drug resistance is urgent. In recent years, new targets and regimens have emerged continuously. This review discusses the fundamental mechanisms of drug resistance in the targeted therapies of HER2-positive breast cancer and summarizes recent research progress in this field, including preclinical and basic research studies.

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“…2 HER2 overexpression is associated with a biologically aggressive tumor phenotype, poor prognosis, increased risk of disease recurrence, and limited benefit from chemotherapy. 1,[3][4][5] HER2-directed therapy is standard of care for HER2-expressing unresectable or metastatic breast cancer, HER2-positive locally advanced or metastatic gastric cancers, colorectal and gastroesophageal junction adenocarcinomas, and HER2-mutant non-small-cell lung cancer. [6][7][8][9] However, many patients with other HER2-expressing solid tumors will progress on standard therapy, with poor prognosis and limited alternatives.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

Meric-Bernstam,

Makker,

Oaknin

et al. 2024

JCO

199

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PURPOSE Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. PATIENTS AND METHODS This open-label phase II study evaluated T-DXd (5.4 mg/kg Q3W) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment, or without alternative treatments. Primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free (PFS), and overall survival (OS). RESULTS primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Median follow-up was 12.75 months. In all patients: ORR, 37.1% (n=99; 95% CI, 31.3–43.2) with responses in all cohorts; median DOR, 11.3 months (95% CI, 9.6–17.8); median PFS, 6.9 months (95% CI, 5.6–8.0); median OS, 13.4 months (95% CI, 11.9–15.5). In patients with central HER2 IHC 3+ expression (n=75): ORR, 61.3% (95% CI, 49.4–72.4); median DOR, 22.1 months (95% CI, 9.6–not reached); median PFS, 11.9 months (95% CI, 8.2–13.0); median OS, 21.1 months (95% CI, 15.3–29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pre-treated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

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CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer

Cited by 26 publications

References 37 publications

CMTM6 maintains B cell-intrinsic CD40 expression to regulate anti-tumor immunity

CMTM6 maintains B cell-intrinsic CD40 expression to regulate anti-tumor immunity

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

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