From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

Abstract

Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancer-related genes. Several therapeutic strategies targeting oncogenic KRAS (KRAS ^onc ) signaling pathways have been suggested, including the inhibition of synthetic lethal interactions, direct inhibition of KRAS ^onc itself, blockade of downstream KRAS ^onc effectors, prevention of post-translational KRAS ^onc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways, targeted RNA replacement, and oncogene-induced senescence. Despite intensive and continuous efforts, KRAS ^onc remains an elusive target for cancer therapy. To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date. An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRAS^onc-signaling targeted therapeutics.

Keywords: Direct inhibition; downstream effectors; drug target sites; oncogenic KRAS; signal transduction; small GTPases; targeting synthetic, lethal interactions; therapeutic strategies.

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KRAS signaling pathways. Different upstream RTKs, regulators (GEFs and GAPs), downstream effectors, and transcription factors are presented along with posttranslational modification of newly synthesized KRAS (gray box) to trafficking modified KRAS (red box) and its association with plasma membrane. Stimulatory effects are shown in black lines and inhibitory effects in red lines. The color yellow shows some of the downstream therapeutic targets mentioned in this article. The asterisk ^* highlights posttranslationally modified KRAS.

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Different therapeutic targets for KRAS driven cancers. The most important of these therapeutic strategies discussed in this article are shown by numbers: (1) Inhibition of transcription by G4 elements. (2) Inhibition of translation through complementary microRNAs. (3) Targeting enzymes posttranslationally modifying KRAS. (4) Targeting KRAS membrane trafficking. (5) Interference with upstream signaling by targeting of receptor tyrosine kinases. (6) Targeting GEFs and RAS activation. (7) Targeting KRAS effectors and downstream signaling pathways. (8) Suppression of synthetic lethal interactions. (9) Targeting inflammatory signaling pathways. (10) Targeting cell cycle progression. (11) Reregulation of metabolic alternations. (12) Reprogramming of stem cell properties. (13) Upregulation of miRs with anti-KRAS activity. Black arrows with blocked red circles are referred to inhibited targets as potential therapeutic approaches.