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

Abstract

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.

Targeting Oncogenic BRAF: Past, Present, and Future

“…Despite remarkable early remission and overall improvement of patient outcome, resistance to RAF/MEK-targeted therapies invariably occurs [5,70,71]. Resistance to therapy can be classified into three categories as intrinsic resistance, adaptive resistance, and acquired resistance [49].…”

“…Many multi-omics efforts have identified alterations in genomic and epigenomic features in tumors, such as DNA mutations, chromosomal copy number, coding and non-coding gene expression, promoter methylation, protein expression, and metabolic activity. A systematic analysis of cancer -omics analysis is now the standard for modern cancer diagnosis, and -omics-informed targeted therapy has become a key component of precision oncology, moving the field beyond general cytotoxic chemotherapy in many tumor types [5].…”

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

“…Regarding immunohistochemistry, receptor tyrosine kinase overexpression, other than c-KIT in LCNEC and SCLC was scarce [25]. Hence, inhibition of tyrosine kinases in SCLC might provide options for personalized medicine in the context of Next-Generation Sequencing (NGS) results for instance [26,27,28,29].…”

Precise prediction of the radiation pneumonitis in lung cancer: an explorative preliminary mathematical model using genotype information

“…to make cancer therapies advanced into targeted therapy and immunotherapy. 31,32 However, in the field of radiotherapy, much less attention has been paid on the genetic features and much work need be done to make personal genetic features as a guiding biomarker for the clinical practice of radiologists. Here we attempt to develop a kind of precision medicine approach that can help radiation oncologists take advantage of genetic features.…”