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Updated: Apr 15, 2026
Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Therapy-induced tumour secretomes promote resistance and tumour progression
Anna C Obenauf1, Yilong Zou2, Andrew L Ji1
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Abstract:
Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.
Insights
Targeted cancer therapy can paradoxically promote drug-resistant cell growth through secreted signals. Combination therapy targeting RAF and PI3K/AKT/mTOR pathways may overcome this resistance and prevent tumor relapse.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Drug resistance limits targeted kinase inhibitor efficacy in cancer.
- Targeted therapies can induce complex signaling networks in cancer cells.
Purpose of the Study:
- Investigate the impact of kinase inhibitors on cancer cell secretomes.
- Determine how therapy-induced secretomes affect drug-resistant and sensitive cancer cells.
- Identify therapeutic strategies to overcome drug resistance.
Main Methods:
- Treatment of human and mouse melanoma and lung adenocarcinoma cells with kinase inhibitors (BRAF, ALK, EGFR).
- Analysis of the secretome produced by drug-stressed cancer cells.
- In situ transcriptome analysis of drug-resistant melanoma cells.
- Evaluation of combination therapy targeting RAF and PI3K/AKT/mTOR pathways.
Main Results:
- Kinase inhibitors induce a tumor-promoting secretome that supports drug-resistant clone expansion and metastasis.
- Vemurafenib-induced secretome in melanoma is driven by FRA1 downregulation.
- Drug-resistant melanoma cells show AKT pathway hyperactivation.
- Combination therapy of RAF and PI3K/AKT/mTOR inhibitors reduced drug-resistant cell outgrowth in BRAF mutant melanoma.
Conclusions:
- Therapeutic inhibition of oncogenic drivers alters cancer cell secretomes, creating a pro-tumor microenvironment.
- This microenvironment paradoxically supports drug-resistant clone expansion.
- Combination therapy targeting key signaling pathways offers a strategy to combat tumor relapse and resistance.
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