Targeting Oncogenic BRAF: Past, Present, and Future.

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies

Emerging application of genomics-guided therapeutics in personalized lung cancer treatment

In lung cancer, genomics-driven comprehensive molecular profiling has identified novel chemically and immunologically addressable vulnerabilities, resulting in an increasing application of precision medicine by targeted inactivation of tumor oncogenes and immunogenic activation of host anti-tumor surveillance as modes of treatment. However, initially profound response of these targeted therapies is followed by relapse due to therapy-resistant residual disease states. Although distinct mechanisms and frameworks for therapy resistance have been proposed, accounting for and upfront prediction of resistance trajectories has been challenging. In this review, we discuss in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the current standing, and challenges associated with genomics-guided strategies for personalized therapy against both oncogenic alterations as well as post-therapy resistance mechanisms. In NSCLC, we catalog the targeted therapy approaches against most notable oncogenic alterations such as epidermal growth factor receptor (EGFR), serine/threonine-protein kinase b-raf (BRAF), Kirsten rat sarcoma viral proto-oncogene (KRAS), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1). For SCLC, currently highly recalcitrant to targeted therapy, we enumerate a range of exciting and maturing precision medicine approaches. Furthermore, we discuss a number of immunotherapy approaches, in combination or alone, that are being actively pursued clinically in lung cancer. This review not only highlights common mechanistic themes underpinning different classes of resistance and discusses tumor heterogeneity as a source of residual disease, but also discusses potential ways to overcome these barriers. We emphasize how an extensive understanding of these themes can predict and improve therapeutic strategies, such as through poly-therapy approaches, to forestall tumor evolution upfront

Emerging application of genomics-guided therapeutics in personalized lung cancer treatment.

In lung cancer, genomics-driven comprehensive molecular profiling has identified novel chemically and immunologically addressable vulnerabilities, resulting in an increasing application of precision medicine by targeted inactivation of tumor oncogenes and immunogenic activation of host anti-tumor surveillance as modes of treatment. However, initially profound response of these targeted therapies is followed by relapse due to therapy-resistant residual disease states. Although distinct mechanisms and frameworks for therapy resistance have been proposed, accounting for and upfront prediction of resistance trajectories has been challenging. In this review, we discuss in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the current standing, and challenges associated with genomics-guided strategies for personalized therapy against both oncogenic alterations as well as post-therapy resistance mechanisms. In NSCLC, we catalog the targeted therapy approaches against most notable oncogenic alterations such as epidermal growth factor receptor (EGFR), serine/threonine-protein kinase b-raf (BRAF), Kirsten rat sarcoma viral proto-oncogene (KRAS), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1). For SCLC, currently highly recalcitrant to targeted therapy, we enumerate a range of exciting and maturing precision medicine approaches. Furthermore, we discuss a number of immunotherapy approaches, in combination or alone, that are being actively pursued clinically in lung cancer. This review not only highlights common mechanistic themes underpinning different classes of resistance and discusses tumor heterogeneity as a source of residual disease, but also discusses potential ways to overcome these barriers. We emphasize how an extensive understanding of these themes can predict and improve therapeutic strategies, such as through poly-therapy approaches, to forestall tumor evolution upfront

Quantitative Framework for Bench-to-Bedside Cancer Research

Bioscience is an interdisciplinary venture. Driven by a quantum shift in the volume of high throughput data and in ready availability of data-intensive technologies, mathematical and quantitative approaches have become increasingly common in bioscience. For instance, a recent shift towards a quantitative description of cells and phenotypes, which is supplanting conventional qualitative descriptions, has generated immense promise and opportunities in the field of bench-to-bedside cancer OMICS, chemical biology and pharmacology. Nevertheless, like any burgeoning field, there remains a lack of shared and standardized framework for quantitative cancer research. Here, in the context of cancer, we present a basic framework and guidelines for bench-to-bedside quantitative research and therapy. We outline some of the basic concepts and their parallel use cases for chemical–protein interactions. Along with several recommendations for assay setup and conditions, we also catalog applications of these quantitative techniques in some of the most widespread discovery pipeline and analytical methods in the field. We believe adherence to these guidelines will improve experimental design, reduce variabilities and standardize quantitative datasets

Targeting Oncogenic BRAF: Past, Present, and Future

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies

Targeting Oncogenic BRAF: Past, Present, and Future.

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies