About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients’ response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.
A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.
The relative success of platinum (Pt)-based chemotherapy
comes
at the cost of severe adverse side effects and is associated with
a high risk of pro-oncogenic activation in the tumor microenvironment.
Here, we report the synthesis of C-POC, a novel Pt(IV) cell-penetrating
peptide conjugate showing a reduced impact against nonmalignant cells.
In vitro and in vivo evaluation using patient-derived tumor organoids
and laser ablation inductively coupled plasma mass spectrometry indicates
that C-POC maintains robust anticancer efficacy while displaying diminished
accumulation in healthy organs and reduced adverse toxicity compared
to the standard Pt-based therapy. Likewise, C-POC uptake is significantly
lowered in the noncancerous cells populating the tumor microenvironment.
This results in the downregulation of versican, a biomarker of metastatic
spreading and chemoresistance that we found upregulated in patients
treated with standard Pt-based therapy. Altogether, our findings underscore
the importance of considering the off-target impact of anticancer
treatment on normal cells to improve drug development and patient
care.
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