Evolution of Molecular Targeted Cancer Therapy: Mechanisms of Drug Resistance and Novel Opportunities Identified by CRISPR-Cas9 Screening

Abstract

Molecular targeted therapy has revolutionized the landscape of cancer treatment due to better therapeutic responses and less systemic toxicity. However, therapeutic resistance is a major challenge in clinical settings that hinders continuous clinical benefits for cancer patients. In this regard, unraveling the mechanisms of drug resistance may identify new druggable genetic alterations for molecularly targeted therapies, thus contributing to improved therapeutic efficacies. The recent rapid development of novel methodologies including CRISPR-Cas9 screening technology and patient-derived models provides powerful tools to dissect the underlying mechanisms of resistance to targeted cancer therapies. In this review, we updated therapeutic targets undergoing preclinical and clinical evaluation for various cancer types. More importantly, we provided comprehensive elaboration of high throughput CRISPR-Cas9 screening in deciphering potential mechanisms of unresponsiveness to molecularly targeted therapies, which will shed light on the discovery of novel opportunities for designing next-generation anti-cancer drugs.

cAMP-Dependent Signaling and Ovarian Cancer

“…Detailed recognition of pathologic signaling at the molecular level provides the mechanistic background for novel therapeutic approaches ( Figure 3 ). For instance, deregulated activation of protein kinases and phosphatases, e.g., ErbB2, EGFR, MAPK, VEGF, mTOR, have become one of the most widely studied tumor therapeutic targets [ 51 , 112 , 113 , 114 , 115 ].…”

The role of T-cells in head and neck squamous cell carcinoma: From immunity to immunotherapy

“…For the last decades, many researchers have been investigating new approaches for the development of biomarker-based treatments that can guide physicians to decisions regarding patient`s outcomes especially in recurrent/metastatic diseases. The discovery and development of specific molecular targets have demonstrated therapeutic potential in cancer treatment, based on signal transduction alterations in cancer cells ( 6 ), mostly applying monoclonal antibodies or tyrosine kinase inhibitors that target specific receptors correlated to proliferative pathways like the epidermal growth factor receptor (EGFR) and angiogenesis characterized by the vascular endothelial growth factor receptor (VEGFR) ( 7 ).…”

Molecular targeted therapy for anticancer treatment

“…Primary (intrinsic) resistance is defined as a refractory status to initial therapy due to intrinsic cellular, genetic, and/or epigenetic alterations. Hyperactivation of compensatory signaling pathways [e.g., truncated HER2 expression (p95HER2) for resistance to anti-HER2 mAbs 38 ; KRAS mutation or MET amplification for resistance to anti-EGFR therapy 38 , 39 ], mutations in kinase domains (e.g., EGFR exon 20 insertion for resistance to anti-EGFR therapy 38 ), isoform switching (e.g., BRAF/CRAF switching for resistance to anti-BRAF therapy 40 ), and metabolic reprogramming 40 during disease development are involved in primary resistance to molecular targeted therapy.…”

“…Human cancers often exhibit substantial intratumor heterogeneity, which is a main driver for emerging acquired therapy resistance as a result of expansion of rare preexisting refractory populations during treatment in initial responders 39 , 41 , 42 . Various molecular and cellular alterations [e.g., development of secondary mutations [EGFR T790M and C797S 38 , 43 , 44 , BCR-ABL T315I 44 , BRAF V600E 40 , 44 , Bruton’s tyrosine kinase (BTK) C418S 44 , anaplastic lymphoma kinase (ALK) G1202R, and ROS1 G2032R and D2033N 44 ], alterations in noncoding RNAs 44 , activation of bypassing signaling pathways, including MET, HER2, type I insulin-like growth factor receptor (IGF-1R), and AXL 43 , 45 , mutations in BRAF, PTEN, PIK3CA, and MAP2K1 43 , 45 , interaction with stromal cells in the tumor microenvironment 43 , 46 , alterations in E3 ubiquitin ligases 47 , reactivation of developmental processes, such as the epithelial-mesenchymal transition (EMT), acquisition of cancer stem cell (CSC)-associated phenotypes, and transdifferentiation to small-cell lung cancer 43 , 48 ] have also been shown to induce acquired therapy resistance.…”