Inhibition of adaptive therapy tolerance in cancer: is triplet mitochondrial targeting the key?

Abstract

Targeted therapies have become a mainstay in the treatment of cancer, but their long‐term efficacy is compromised by acquired drug resistance. Acquired therapy resistance develops via two phases—first through adaptive development of nongenetic drug tolerance, which is followed by stable resistance through the acquisition of genetic mutations. Drug tolerance has been described in practically all clinical cancer treatment contexts, and detectable drug‐tolerant tumors are highly associated with treatment relapse and poor survival. Thereby, novel therapeutic strategies are needed to overcome cancer therapy tolerance. Recent studies have identified a critical role of mitochondrial mechanisms in defining cancer cell sensitivity to targeted therapies and the surprising effects of established cancer therapies on mitochondria. Here, these recent studies are reviewed emphasizing an emerging concept of triplet therapies including three compounds targeting different cancer cell vulnerabilities but including at least one compound that targets the mitochondria. These mitochondria‐targeting triplet therapies have very promising preclinical effects in overcoming cancer therapy tolerance. Potential strategies of how to overcome challenges in the clinical translation of mitochondria‐targeting triplet therapies are also discussed.

SSBP1 is a novel prognostic marker and promotes disease progression via p38MAPK signaling pathway in multiple myeloma

“…Currently, mitochondrialtargeting biomolecules showed promise therapeutic direction in cancer cells. 33,34 However, mitochondria-targeting anticancer drugs…”

“…Thus, it would be reasonable to speculate that targeted suppression of SSBP1 expression induces apoptosis of MM cells via upregulation of the mtROS/p38MAPK signaling (Figure ). Currently, mitochondrial‐targeting biomolecules showed promise therapeutic direction in cancer cells 33,34 . However, mitochondria‐targeting anticancer drugs still limited.…”

Targeting drug‐tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

“…In a melanoma with BRAF mutation, slow‐cycling persister cells display an increased level of mitochondrial oxidative‐ATP‐synthetic gene expression after treatment as well as improve their susceptibility to mitochondrial respiratory chain inhibition 70,191 . Such mitochondrial respiration dependence is detected in DTCs derived from various types of cancer, such as NSCLC, BC, and GC 53,59,192 . In the DTCs derived from these types of cancer, the increased levels of ROS and hydrogen peroxide are ascribed to fatty acid (FA) oxidation and mitochondrial respiration hypermetabolism 59,66,70,193–198 .…”

Molecular Oncology and the EACR: new partners in communicating and supporting cancer research

“…In further connections between the EACR and Molecular Oncology , the journal has recently started to publish a new article type entitled ‘Viewpoints from the EACR’, in which researchers connected to the EACR are invited to write commentaries on recent developments or contentious topics in cancer research and their transformative opinions. Two of these have already been published [ 2 , 3 ], and the aim is for this to be a recurring feature in future issues.…”