AMG 510: the kryptonite of mutant KRASG12C

Over three decades of cancer therapy research have been dedicated to investigating the most frequently mutated oncogene: KRAS. Approximately one million cancer deaths per year worldwide are traced to mutations in KRAS, which promote tumour formation and survival. Countless failed anti-KRAS therapies have deemed KRAS “undruggable”, as traditional medicinal chemistry seemed ill-equipped to design drugs against proteins, such as KRAS, with no obvious binding sites or “pockets”. Recently, the clinical development of a covalently binding small molecule known as AMG 510 has suggested that it may be the most promising anti-KRAS therapy. KRAS resides within the RAS family of GTPase proteins described as on/off switches for cell growth and proliferation. The desire to specifically target mutant KRASG12C stems from its presence in some of the deadliest cancers, such as colorectal, pancreatic, and lung adenocarcinomas. The substitution of guanine with nucleophilic cysteine disrupts the GTPase activity of KRAS so that it is persistently active, forcing cells into a hyperproliferative state that increases susceptibility to mutation.</p

AMG 510: the kryptonite of mutant KRASG12C

Over three decades of cancer therapy research have been dedicated to investigating the most frequently mutated oncogene: KRAS. Approximately one million cancer deaths per year worldwide are traced to mutations in KRAS, which promote tumour formation and survival. Countless failed anti-KRAS therapies have deemed KRAS “undruggable”, as traditional medicinal chemistry seemed ill-equipped to design drugs against proteins, such as KRAS, with no obvious binding sites or “pockets”. Recently, the clinical development of a covalently binding small molecule known as AMG 510 has suggested that it may be the most promising anti-KRAS therapy. KRAS resides within the RAS family of GTPase proteins described as on/off switches for cell growth and proliferation. The desire to specifically target mutant KRASG12C stems from its presence in some of the deadliest cancers, such as colorectal, pancreatic, and lung adenocarcinomas. The substitution of guanine with nucleophilic cysteine disrupts the GTPase activity of KRAS so that it is persistently active, forcing cells into a hyperproliferative state that increases susceptibility to mutation.</p

The promise and potential of the adeno-associated viral vector in gene therapy

The adeno-associated virus (AAV) vector system has emerged as one of the most attractive methods of gene therapy, namely for its favourable safety profile, non-pathogenicity in humans, and efficient delivery of genetic material. As a vehicle of gene delivery, it can deliver a gene or modify an existing one by infecting and transducing cells, most notably those that are post mitotic. Conveniently, the adeno-associated virus’s capsid can be manipulated and serotypes harnessed, so as to more efficiently target tissue-specific diseases. Development and maturation of the AAV system has seen its integration with other gene therapy technologies such as the CRISPR-Cas system, and RNA interference, further enhancing the power and variety of its therapeutic applications. Several clinical trials involving the AAV system are underway. Its use in the treatment of a progressive motor neuron disease, spinal muscular atrophy type 1, is just one of several examples of its translational success. However, the AAV system has limitations that must be circumvented in order to maximise its effectiveness in humans; host anti-viral responses and the restricting carrying capacity of the vector are examples of such barriers that are being actively tackled by multidisciplinary teams in hopes of optimising and perfecting its therapeutic prowess </p