Therapy-induced tumour secretomes promote resistance and tumour progression

Abstract

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer1,2. Here we show that targeted therapy with BRAF, ALK, or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed melanoma and lung adenocarcinoma cells. This therapy-induced secretome (TIS) 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 vemurafenib reactive secretome in melanoma is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of multiple signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and PI3K/AKT/mTOR pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant melanoma tumours, 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.

A price to pay for tumor regression

“…Further pathway analysis of transcripts induced in drug-resistant cells highlighted the PI3K-AKT pathway as a key mediator of proliferation of drug-resistant cancer cells. Consistent with this, the authors showed that inhibition of the PI3K-AKT pathway with small-molecule drugs reduced the growth-stimulatory effect of the TIS both in vitro and in vivo, providing a potential combination strategy to counter the effects of the TIS [3].…”

“…Others have highlighted the role of tumor stroma in induction of epithelial to mesenchymal transition in the cancer cells, which in turn can cause drug resistance. In a recent study, Obenauf and colleagues add a new and unexpected dimension to paracrine drug resistance signaling [3].…”

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

“…An alternative possibility is that cells treated with targeted therapies secrete factors that promote the survival of drug-sensitive cells ( 45 ), suggesting that resistant cells can sustain sensitive cells and therefore persist as a minority population in the resistant tumor.…”

Orchestration of the crosstalk between astrocytes and cancer cells affects the treatment and prognosis of lung cancer sufferers with brain metastasis

“…Massagué and his colleagues two opposite roles for astrocytes in brain metastasis in separate works: dispelling cancer cells entering the brain parenchyma (7,13) and promoting the progression of metastasis in the brain (8,14). The contact with astrocytes leads to up-regulated expression of multiple genes in the cancer cells (15), including several survival genes that are in charge of the increased resistance of cancer cells to cytotoxic drugs (12).…”

“…As it explicates, circulating cancer cells must overcome many obstacles to colonize in brain (6). However, once the distinctive biology of metastases is established in brain, the host microenvironment will play a "sanctuary" role in promoting metastatic growth and treatment resistance (7), and then current treatments frequently fail to provide durable responses (8). An improved understanding of the crosstalk between microenvironment and cancer cells is needed to prevent and treat metastatic cancer (9).…”