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Cyclin‐dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF‐1α‐mediated responses to hypoxia. These MYC‐driven adaptations to CDK4/6 inhibition render cancer cells highly sensitive to inhibitors of MYC, glutaminase or mTOR and to hypoxia, demonstrating that metabolic adaptations to antiproliferative drugs unveil new vulnerabilities that can be exploited to overcome acquired drug tolerance and resistance by cancer cells. Synopsis MYC is a key driver of cancer cell metabolic adaptations after CDK4/6 inhibition, which includes upregulation of glutaminase 1 (GLS1) and mTOR‐dependent pathways. Combined inhibition of these targets synergistically and selectively inhibits cancer cell growth. CDK4/6 inhibition enhances glycolysis and mitochondrial metabolism and function. CDK4/6‐Cyclin D1 complexes phosphorylate MYC while inhibition of CDK4/6 stabilizes MYC, driving the ensuing metabolic reprogramming. MYC accumulation upregulates GLS1 and mTOR and blunts hypoxic response. Combined CDK4/6 and GLS1 inhibition has selective synergic effects on cancer cells. Graphical Abstract MYC is a key driver of cancer cell metabolic adaptations after CDK4/6 inhibition, which includes upregulation of glutaminase 1 (GLS1) and mTOR‐dependent pathways. Combined inhibition of these targets synergistically and selectively inhibits cancer cell growth.

The pentose phosphate pathway (PPP) plays an essential role in the metabolism of breast cancer cells for the management of oxidative stress and the synthesis of nucleotides. 6-phosphogluconate dehydrogenase (6PGD) is one of the key enzymes of the oxidative branch of PPP and is involved in nucleotide biosynthesis and redox maintenance status. Here, we aimed to analyze the functional importance of 6PGD in a breast cancer cell model. Inhibition of 6PGD in MCF7 reduced cell proliferation and showed a significant decrease in glucose consumption and an increase in glutamine consumption, resulting in an important alteration in the metabolism of these cells. No difference in reactive oxygen species (ROS) production levels was observed after 6PGD inhibition, indicating that 6PGD, in contrast to glucose 6-phosphate dehydrogenase, is not involved in redox balance. We found that 6PGD inhibition also altered the stem cell characteristics and mammosphere formation capabilities of MCF7 cells, opening new avenues to prevent cancer recurrance after surgery or chemotherapy. Moreover, inhibition of 6PGD via chemical inhibitor S3 resulted in an induction of senescence, which, together with the cell cycle arrest and apoptosis induction, might be orchestrated by p53 activation. Therefore, we postulate 6PGD as a novel therapeutic target to treat breast cancer.

With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, we employed a strategy for the rational identification of targetable metabolic vulnerabilities. This strategy involved first a thorough metabolic characterisation of same-patient-derived cell lines from primary colon adenocarcinoma (SW480), its lymph node metastasis (SW620) and a liver metastatic derivative (SW620-LiM2), and second, using a novel multi-omics integration workflow, identification of metabolic vulnerabilities specific to the metastatic cell lines. We discovered that the metastatic cell lines are selectively vulnerable to the inhibition of cystine import and folate metabolism, two key pathways in redox homeostasis. Specifically, we identified the system xCT and MTHFD1 genes as potential therapeutic targets, both individually and combined, for combating mCRC.

Cyclin‐dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF‐1α‐mediated responses to hypoxia. These MYC‐driven adaptations to CDK4/6 inhibition render cancer cells highly sensitive to inhibitors of MYC, glutaminase or mTOR and to hypoxia, demonstrating that metabolic adaptations to antiproliferative drugs unveil new vulnerabilities that can be exploited to overcome acquired drug tolerance and resistance by cancer cells.

Therapeutic resistance in cancer emerges from genetic or epigenetic mechanisms that enable cell survival under drug pressure. While several resistance mechanisms to cyclin-dependent kinase inhibitors have been identified, acquired resistance is still a therapeutic challenge. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDK4/6 inhibitor, or Telaglenestat, a glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenestat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenestat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenestat. Our findings reveal that Palbociclib and Telaglenestat combination can effectively forestall acquired resistance to Palbociclib.Competing Interest StatementThe authors have declared no competing interest.

Passive states are defined as those states that do not allow for work extraction in a cyclic (unitary) process. Within the set of passive states, thermal states are the most stable ones: they maximize the entropy for a given energy, and similarly they minimize the energy for a given entropy. Here we find the passive states lying in the other extreme, i.e., those that maximize the energy for a given entropy, which we show also minimize the entropy when the energy is fixed. These extremal properties make these states useful to obtain fundamental bounds for the thermodynamics of finite-dimensional quantum systems, which we show in several scenarios.