Cancer single pathways inhibitors: More resistance than durable success in the clinic

Twelve years after trastuzumab (breast cancer, gastric cancer) efficacy assessment, criticism is being increasingly against initial overenthusiasm. Several lessons we can take. First, a few only other targeted drugs have demonstrated antitumor activity leading to significant overall survival benefit: imatinib and vemurafenib (PLX4032). Second, response and survival benefit is nearly always occurred only in predictive molecular markers-based selected patients (HER2-positive, without BCR-ABL1 mutation, BRAF-V600E mutation respectively). Third, for most other of roughly 33 approved monoclonal antibodies or tyrosine kinases inhibitors only a progression-free but not overall survival benefit observed. For example disappointing results for cetuximab provide now phase 3 randomized trials even for KRAS-wild-type selected patients in the adjuvant or metastatic setting. How could this intrinsic or acquired resistance be overcome? Is a durable responsiveness to signal transduction inhibitors resulting in long-term overall survival benefit achievable? In this perspective advances and challenges of targeted cancer therapies are discussed. Moreover, based on latest advances and scientific evidence on dynamics of network biology as well as signaling transduction pathways network driving gene expression functional networks, cellular and patient's outcomes, it is explored the potential of next-generation drugs and biomarkers to achieve in the foreseeable future long-term durable response and cure of cancer.