Abstract
The small heat‐shock protein of 27 kDa (HSP27) is highly expressed in many cancers and is associated with aggressive tumour behaviour, metastasis, poor prognosis and resistance to chemotherapy. We aimed at assessing the role of HSP27 in modulating responses to target therapies. We selected several oncogene‐addicted cancer cell lines, which undergo either cell cycle blockade or cell death in response to agents that target the specific oncogene. Surprisingly, HSP27 suppression alone resulted in the apoptotic death of MET‐addicted EBC‐1 lung cancer cells, epidermal growth factor receptor (EGFR)‐addicted colorectal carcinoma (CRC) DiFi cells and BRAF‐addicted CRC COLO205 and OXCO‐1 and melanoma COLO741 cells, all of which also undergo death when treated with the specific targeted agent. In other cell lines, such as MET‐addicted gastric carcinoma MKN45 and EGFR‐addicted CRC SW48 lines, where oncogene inhibition only blocked proliferation, HSP27 knockdown made targeted agents switch from cytostatic to cytotoxic activity. Mechanistically, the more the cells were susceptible to HSP27 suppression, the more they were primed for death, as demonstrated by increased levels of mitochondrial outer membrane permeabilization. Priming for death was accompanied by the increase in pro‐apoptotic proteins of the BCL2 family and of active caspase‐3 and lamin B. Together, these data suggest that oncogene‐addicted cells require HSP27 for survival and that HSP27 might interfere with the effectiveness of targeted agents.
Highlights
The most successful current paradigms in targeted therapy consist of directly inhibiting mutated or amplified oncogenes, to which the cancer cells, but not the normal cell counterpart, are ‘addicted’
MET oncogene-addicted carcinoma cells are susceptible to heat-shock protein of 27 kDa (HSP27) suppression
This study shows that HSP27 protects oncogeneaddicted cancer cells from the activation of the mitochondrial pathway of apoptosis, measured as increased mitochondrial outer membrane permeabilization (MOMP) and increased levels of pro-apoptotic effector proteins
Summary
The most successful current paradigms in targeted therapy consist of directly inhibiting mutated or amplified oncogenes, to which the cancer cells, but not the normal cell counterpart, are ‘addicted’. The most convincing evidence came out, supporting the concept of ‘oncogene addiction’, as there are examples of the therapeutic efficacy of antibodies or drugs targeting specific oncogenes. Among known oncogenes, those encoding kinases account for a significant number of molecular targets exploited today in the clinic. Those encoding kinases account for a significant number of molecular targets exploited today in the clinic Their targeting agents might be small-molecule inhibitors, which block kinase enzymatic activity or signalling (for a review, see Gross et al, 2015). The V600 BRAF mutation is the most common in melanoma, and mutation-specific inhibitors are effectively used to treat melanoma and some of the nonmelanoma cancers with the same mutation (Hyman et al, 2015)
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