Targeting TRK: A fast-tracked application of precision oncology and future directions.

The NTRK genes encode the tropomyosin-related receptor tyrosine kinases TrkA, TrkB and TrkC. TRK receptors regulate the proliferation, differentiation, and survival of many neuronal and non-neuronal glial cells during embryogenesis, thus playing a critical role in synaptic plasticity and the development of nociceptive pathways. Recurrent genomic alterations in NTRK genes, typically fusions involving the 3' region encoding the kinase domain juxtaposed to 5' sequences from numerous partner genes, occur at a low frequency in a wide diversity of adult and pediatric cancers. The contributions of the resulting constitutively activated kinase to oncogenesis and cancer progression are being elucidated. Larotrectinib and entrectinib are potent first-generation TRK inhibitors with IC50 values in the nanomolar range across cancer cell lines harboring NTRK fusions. Larotrectinib is highly selective for TRK receptors, whereas entrectinib also potently inhibits ROS1 and ALK. Clinical trials of both drugs demonstrated significant and durable responses in patients with tumors harboring NTRK alterations, leading to first of its kind cancer agnostic FDA approvals in the United States for drugs targeting a genomic alteration. Unfortunately, acquired resistance inevitably develops. The second-generation TRK inhibitors selitrectinib and repotrectinib are designed to overcome known mechanisms of resistance.

Distribution of cancer genes in human chromosomes.

We increasingly recognize the importance of alterations in DNA in the development of cancer. Beginning with the first somatic mutation identified in a urinary bladder carcinoma cell line, recombinant-DNA technology has led to an explosion of this field, bringing a wealth of data, yet to be fully analyzed. As the number of putative cancer genes has grown several groups have compiled lists of cancer genes with the Catalogue Of Somatic Mutations In Cancer, list as one of several highly regarded. With an interest in the distribution of cancer genes in human chromosomes and discerning whether some chromosomes predominated in cancer gene content, we undertook this review of their distribution in the modern-day human genome. We conclude that cancer genes are uniformly distributed across all human chromosomes having been accreted to the evolving human genome likely in a random fashion over the millennia.

Emerging Therapeutic Implications of STK11 Mutation: Case Series.

STK11 was first recognized as a tumor suppressor gene in the late 1990s based on linkage analysis of patients with Peutz-Jeghers syndrome. STK11 encodes LKB1, an intracellular serine-threonine kinase involved in cellular metabolism, cell polarization, regulation of apoptosis, and DNA damage response. Recurrent somatic loss-of-function mutations occur in multiple cancer types, most notably in 13% of lung adenocarcinomas. Recent reports indicate that KRAS-mutant non-small cell lung cancers harboring co-mutations in STK11 do not respond to PD-1 axis inhibitors. We present three patients with STK11-mutated tumors and discuss the proposed mechanisms by which germline and somatic alterations in STK11 promote carcinogenesis, potential approaches for therapeutic targeting, and the new data on resistance to immune checkpoint inhibitors. KEY POINTS: STK11 is a tumor suppressor gene, and loss-of-function mutations are oncogenic, due at least in part to loss of AMPK regulation of mTOR and HIF-1-α. Clinical trials are under way, offering hope to patients whose STK11-mutated tumors are refractory and/or have progressed on chemotherapeutic regimens. Whether gastrointestinal cancers with STK11 loss of function will show the same outcome and potential refractoriness to immune therapy that were reported for lung cancer is unknown. However, physicians managing such patients should consider the experience in lung cancer, particularly outside the context of a clinical trial. In the CheckMate-057 trial lung tumors harboring co-mutations in KRAS and STK11 had an inferior response to PD-1 axis inhibitors. Coupled with the observation that STK11-mutated tumors were found to have a cold immune microenvironment regardless of KRAS status, the conclusion could extend to KRAS wild-type tumors with STK11 mutation. Current data suggest that the use of PD-1 axis inhibitors may be ill advised in the presence of STK11 mutation.

CDK4/6 Inhibition as a therapeutic strategy in breast cancer: palbociclib, ribociclib, and abemaciclib.

With 40,920 American women expected to die from breast cancer in 2018 and global health estimates that more than 508,000 women died in 2011 from this disease, the identification of novel therapeutic strategies for the treatment of breast cancer cannot be ignored. A breakthrough class of cancer drugs that has emerged in recent years and has had an impact in the treatment of breast cancer are the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, with palbociclib the first in class to have received regulatory approval for breast cancer. In this article we will compare and contrast three CDK4/6 inhibitors - palbociclib, ribociclib and abemaciclib - that have received regulatory approval for the treatment of metastatic breast cancer. Ribociclib and abemaciclib developed after the success of palbociclib represent examples of "me-too" therapies increasingly being deployed in oncology.