Targeting SRC Family Kinases in Mesothelioma: Time to Upgrade

Our plain-English summary of Targeting SRC Family Kinases in Mesothelioma: Time to Upgrade, by P. Indovina, I.M. Forte, F. Pentimalli, et al (Cancers, 2020).

The study

• Authors: P. Indovina, I.M. Forte, F. Pentimalli, A. Giordano
• Journal: Cancers
• Published: 2020;12(7)
• Type of article: Review
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Abstract: Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM.

In plain English

This is a review, not a new study. The authors summarized published laboratory work and two clinical trials on SRC family kinases (SFKs), enzymes that studies have reported to be overactive in malignant mesothelioma, and on drugs that block them, mainly dasatinib. In the studies reviewed, SFK activation was associated with a more advanced stage of mesothelioma. SFK-blocking drugs had antitumor effects in mesothelioma cell lines and made the cells more sensitive to cisplatin and pemetrexed. The first cited trial was a phase II trial of 43 patients with unresectable mesothelioma no longer controlled by platinum and pemetrexed. In that trial the disease control rate was 32.6%, and progression-free survival at 24 weeks was 23%, below the 42% set in advance. The second cited trial gave dasatinib before surgery to 24 patients with resectable mesothelioma and saw no significant responses. The authors concluded that SFKs are promising targets but that the complexity of their signaling hinders clinical use. They cautioned that the laboratory drugs also block other enzymes, that laboratory models are limited, and that the trials enrolled unselected patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published preclinical and clinical studies on SRC family kinases (SFKs) and SFK inhibitors in malignant mesothelioma (MM)
• Who was studied: Published studies, not new patients: laboratory studies in MM cell lines and tissue samples, plus two clinical trials of dasatinib in MM patients (43 patients with unresectable MM; 24 patients with resectable MM)
• Exposure: Not an exposure study. The review covers drugs that inhibit SFKs (and other kinases), chiefly dasatinib, plus other inhibitors such as SU6656, PP2 and pyrazolo-[3,4-d]-pyrimidine compounds developed by the authors' group
• Main results:
  • In cited studies of MM tissue, SFK activation was associated with a more advanced pathologic stage and the presence of metastases
  • In cited cell-line studies, the SFK inhibitor SU6656 enhanced cisplatin cytotoxicity in MM cells
  • In a cited cell-line study, dasatinib made MM cells more sensitive to pemetrexed
  • In the cited phase II trial of dasatinib as second-line treatment (43 patients with unresectable MM), the overall disease control rate was 32.6% and progression-free survival at 24 weeks was 23%, below the prespecified 42% needed to declare the regimen worthy of further study
  • A second cited trial gave dasatinib as a neoadjuvant agent (before surgery) to 24 patients with resectable MM
  • In the neoadjuvant trial, no significant responses were seen after the short period of dasatinib therapy
  • In the neoadjuvant trial, two patients who received maintenance dasatinib remained disease-free during treatment (18.5 and 31.5 months), but their MM progressed when dasatinib was stopped
• The authors' conclusion: The authors concluded that SFKs are promising therapeutic targets for MM, but that the complexity of their signaling pathways hinders translating SFK inhibitors into the clinic. They called for predictive markers to select patients, more faithful preclinical models and rational drug combinations.
• Limitations the authors state:
  • The authors caution that the preclinical data should be interpreted carefully because the SFK inhibitors used also target other kinases
  • The authors note that most preclinical models are limited and do not represent the complexity of MM
  • The authors note that most clinical studies of SFK inhibitors, including the MM trials, involved unselected patients, which they consider a likely reason for the disappointing results

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Prognosis, Clinical Trial, Unresectable.

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