Targeting KRAS G12C Induces Collateral Dependency
Direct KRAS G12C inhibitors are an exciting class of agents now entering the clinic. However, resistance mechanisms to these inhibitors and how to target these mechanisms are not well defined. Lou and colleagues describe a class of genetic interactions that are only required in the setting of oncogene inhibition that they term collateral dependencies (CD). CDs were identified in both lung and pancreatic cancer cell lines utilizing a genome-scale CRISPR screen and found to be distinct from synthetic lethal dependencies. They demonstrate that CDs work through two major mechanisms, either through increased drug engagement or decreased downstream survival signaling. Inhibition of either of these mechanisms with EGFR or CDK4/6 inhibitors, respectively, increased the efficacy of a KRAS inhibitor.
Expert Commentary: This study describes the existence of collateral dependencies for KRAS G12C inhibitors and suggests novel therapeutic combinations that could improve outcomes in the clinic.
BET-Bromodomain Inhibitors in Medulloblastoma
MYC-amplified group 3 medulloblastoma is an aggressive brain tumor that is refractory to intensive multimodal therapy. While BET-bromodomain inhibition (BETi) shows preclinical promise, mechanisms of action and ultimately for resistance are unclear. Bandopadhayay and colleagues combined expression profiling, genome-scale CRISPR/Cas9-mediated loss-of-function, and cDNA-driven rescue screens, together with cell-based models. Using this integrative approach, the authors identified several bHLH/homeobox transcription factors and cell-cycle regulators as mediators of BETi's response and resistance. These genes either regulated cell-cycle progression or neuronal differentiation programs. Furthermore, the authors demonstrated that cells that acquire drug tolerance express lineage-specific bHLH/homeobox transcription factors and a more neuronally differentiated phenotype. Yet, the cells did not differentiate terminally, had sustained CCND2 expression, and maintained proliferative capacity. Importantly, combined CDK and BET inhibition attenuated resistance in xenograft tumor models.
Expert Commentary: This data supports the combination of cell-cycle inhibitors with BETi for treatment of MYC-amplified medulloblastoma.
Tissue-Specific Oncogenic Activity of KRAS-A146T
Different mutations in the gene encoding the small-GTP binding protein KRAS are found in distinct cancers, where they have differential prognostic significance. Poulin and colleagues show that unlike KRAS-Gly12 mutants, which attenuate GTP hydrolysis, KRAS-A146T mutants increase intrinsic RAS activity via accelerated GTP exchange. They next compared mice engineered to mimic the expression of such KRAS mutations in a tissue-specific manner. While KRAS-A146T mice exhibited an attenuated hyperproliferative phenotype in the colon, relative to mice expressing KRAS-G12, KRAS-A146T showed little effect in the pancreas, where KRAS-A146T mutations are typically not found. In an APC mutant background, the different KRAS mutations resulted in histologically similar tumors. However, mice exhibited distinct survival rates similar to what is observed in colorectal cancer patients. The various KRAS mutations altered a significant number of distinct signaling processes in a tissue-specific manner, and these changes were validated using patient-derived colorectal cancer cells and datasets.
Expert Commentary: Distinct KRAS mutations exhibit different mechanisms of activation that drive specific alterations in signaling networks, resulting in distinct therapeutic vulnerabilities.
Accurate Modeling of Human Medulloblastoma
To determine if medulloblastoma could be modeled in human neuroepithelial stem (NES) cells, Huang and colleagues differentiated induced pluripotent stem cells (iPSC) from a karyotypically normal adult into NES cells. When transduced with MYCN and subsequently injected into the hindbrain, mice developed tumors resembling Sonic hedgehog (SHH) medulloblastoma. NES cells from a patient with a germline PTCH1 mutation (Gorlin syndrome) also generated SHH medulloblastoma. Expression of a DDX3X mutant, a common sporadic mutation in adult medulloblastoma, accelerated tumorigenesis. Mutational and copy number analysis revealed no additional events acquired by the reprogrammed NES, suggesting that the mutations introduced drive tumorigenesis.
Expert Commentary: Accurate modeling of human brain tumors in mice poses a formidable challenge, and transgenic models do not always faithfully recapitulate the human disease. This study provides evidence that human medulloblastoma can be modeled using reprogrammed human iPSC that epigenetically and genetically resemble the human condition and provides a crucial resource to generate new therapies for medulloblastoma.
GAD65 Promotes CRPC Development
Transition from an androgen-dependent to a castration-resistant state is a defining event in the progression of prostate cancer. Gao and colleagues compared metabolic pathways between patient-derived xenograft models for isogenic human androgen-dependent and castration-resistant prostate cancer (CRPC) and found increased GABA shunt activity due to GAD65 activation in CRPC. GAD65 selectively promoted androgen receptor nuclear retention in CRPC. Mechanistic investigations showed that GABA bound to the androgen receptor in the nucleus by facilitating its association with the nuclear zinc finger protein ZNHIT3. GAD65 knockdown decreased the growth of multiple established CRPC xenografts and markedly delayed the time to emergence of castration resistance.
Expert Commentary: This study reports metabolic alterations that allow prostate cancer cells to survive upon androgen deprivation and identifies the GABA-producing enzyme GAD65 as a potential new therapeutic target in the treatment of CRPC.
Microglia-Astrocyte Cross-talk in Glioblastoma
Although the interaction of brain tumors with cells in the surrounding microenvironment plays an important role in tumor development, the nature of these interactions is poorly understood. Henrik Heiland and colleagues now show that microglia-astrocyte cross-talk in glioblastoma contributes to an immunosuppressive environment. This is mediated by microglia-dependent JAK/STAT activation of tumor-associated astrocytes resulting in secretion of the anti-inflammatory cytokine IL10. Treatment with a JAK inhibitor reduced tumor growth in an organotypic brain slice model, with a concomitant reduction in activated astrocytes and a change in the balance of pro- and anti-inflammatory cytokines.
Expert Commentary: Understanding how host cells control the inflammatory tumor environment is important in realizing the potential of immune therapies, which to date have been unsuccessful in glioblastoma.
Henrik Heiland K, Ravi VM, Behringer SP, Frenking JH, Wurm J, Joseph K, et al. Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nat Commun 2019;10:2541. doi: 10.1038/s41467-019-10493-6.
Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.