Two complementary studies in Nature Communications define a critical role for the anti-apoptotic protein MCL-1 as a driver of adaptive survival in tumor cells treated with oncogene targeted ...therapies, providing a rationale for combining these agents with newly developed MCL-1 inhibitors in the clinic.
Precision oncology requires an understanding of the genes and pathways that dictate therapeutic response. Through specialized analysis of drug sensitivity patterns across hundreds of genomically ...annotated cancer cell lines, specific and actionable drivers of intrinsic resistance have been identified.
Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed ...that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacologic approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients.
Imaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while ...reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.
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•Oxidation of lactate allows breast cancer cells to withstand fluctuations in glucose availability•ERRα antagonists disrupt mitochondrial function, inhibit lactate utilization, and compromise cancer cell viability•Breast cancer cells utilizing lactate are insensitive to PI3K/mTOR inhibitors•ERRα antagonists increase the activity of clinically relevant PI3K/mTOR inhibitors
Park et al. find that breast cancer cells can use lactate as a respiratory fuel when glucose is limiting, and that this metabolic adaptation is associated with resistance to PI3K inhibitors. However, drug efficacy can be restored by disrupting mitochondrial function using antagonists of the nuclear receptor ERRα.
Wnt signaling regulates the balance between stemness and differentiation in multiple tissues and in cancer. RNF43-mutant pancreatic cancers are dependent on Wnt production, and pharmacologic blockade ...of the pathway, e.g., by PORCN inhibitors, leads to tumor differentiation. However, primary resistance to these inhibitors has been observed. To elucidate potential mechanisms, we performed in vivo CRISPR screens in PORCN inhibitor-sensitive RNF43-mutant pancreatic cancer xenografts. As expected, genes in the Wnt pathway whose loss conferred drug resistance were identified, including APC, AXIN1, and CTNNBIP1. Unexpectedly, the screen also identified the histone acetyltransferase EP300 (p300), but not its paralog, CREBBP (CBP). We found that EP300 is silenced due to genetic alterations in all the existing RNF43-mutant pancreatic cancer cell lines that are resistant to PORCN inhibitors. Mechanistically, loss of EP300 directly downregulated GATA6 expression, thereby silencing the GATA6-regulated differentiation program and leading to a phenotypic transition from the classical subtype to the dedifferentiated basal-like/squamous subtype of pancreatic cancer. EP300 mutation and loss of GATA6 function bypassed the antidifferentiation activity of Wnt signaling, rendering these cancer cells resistant to Wnt inhibition.
While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly ...understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-X
, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-X
+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-X
, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics.
Nonlinear kernel regression models are often used in statistics and machine learning because they are more accurate than linear models. Variable selection for kernel regression models is a challenge ...partly because, unlike the linear regression setting, there is no clear concept of an effect size for regression coefficients. In this article, we propose a novel framework that provides an effect size analog for each explanatory variable in Bayesian kernel regression models when the kernel is shift-invariant-for example, the Gaussian kernel. We use function analytic properties of shift-invariant reproducing kernel Hilbert spaces (RKHS) to define a linear vector space that: (i) captures nonlinear structure, and (ii) can be projected onto the original explanatory variables. This projection onto the original explanatory variables serves as an analog of effect sizes. The specific function analytic property we use is that shift-invariant kernel functions can be approximated via random Fourier bases. Based on the random Fourier expansion, we propose a computationally efficient class of Bayesian approximate kernel regression (BAKR) models for both nonlinear regression and binary classification for which one can compute an analog of effect sizes. We illustrate the utility of BAKR by examining two important problems in statistical genetics: genomic selection (i.e., phenotypic prediction) and association mapping (i.e., inference of significant variants or loci). State-of-the-art methods for genomic selection and association mapping are based on kernel regression and linear models, respectively. BAKR is the first method that is competitive in both settings. Supplementary materials for this article are available online.
The mechanistic target of rapamycin (mTOR) plays a key role in normal and malignant cell growth. However, pharmacologic targeting of mTOR in cancer has shown little clinical benefit, in spite of ...aberrant hyperactivation of mTOR in most solid tumors. Here, we discuss possible reasons for the reduced clinical efficacy of mTOR inhibition and highlight lessons learned from recent combination clinical trials and approved indications of mTOR inhibitors in cancer. We also discuss how the emerging systems level understanding of mTOR signaling in cancer can be exploited for the clinical development of novel multimodal precision targeted therapies and immunotherapies aimed at achieving tumor remission.
Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the ...mitochondrial dynamics network also result in specific therapeutic vulnerabilities. In particular, through distinct mechanisms, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics, a class of compounds that induce apoptosis through inhibition of IAPs and for which robust sensitivity biomarkers remain to be identified. Further, because driver oncogenes exert dominant control over mitochondrial dynamics, oncogene-targeted therapies can be used to sensitize tumors to SMAC mimetics via their effects on fission/fusion dynamics. Collectively, these data demonstrate that perturbations to the mitochondrial dynamics network induce targetable vulnerabilities across diverse human tumors and, more broadly, suggest that the altered structures, activities, and trafficking of cellular organelles may facilitate additional cancer therapeutic opportunities.
During apoptosis, mitochondrial outer membrane permeabilization (MOMP) enables certain mitochondrial matrix macromolecules to escape into the cytosol. However, the fate of mitochondrial RNA (mtRNA) ...during apoptosis is unknown. Here, we demonstrate that MOMP results in the cytoplasmic release of mtRNA and that executioner caspases-3 and -7 (casp3/7) prevent cytoplasmic mtRNA from triggering inflammatory signaling. In the setting of genetic or pharmacological casp3/7 inhibition, apoptotic insults result in mtRNA activation of the MDA5/MAVS/IRF3 pathway to drive Type I interferon (IFN) signaling. This pathway is sufficient to activate tumor-intrinsic Type I IFN signaling in immunologically cold cancer models that lack an intact cGAS/STING signaling pathway, promote CD8
T-cell-dependent anti-tumor immunity, and overcome anti-PD1 refractoriness in vivo. Thus, a key function of casp3/7 is to inhibit inflammation caused by the cytoplasmic release of mtRNA, and pharmacological modulation of this pathway increases the immunogenicity of chemotherapy-induced apoptosis.
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