Targeting CDK4/6 in patients with cancer

Abstract

The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components. Due to the importance of CDK4/6 activity in cancer cells, CDK4/6 inhibitors have emerged as promising candidates for cancer treatment. Moreover, combination of a CDK4/6 inhibitor with other targeted therapies may help overcome acquired or de novo treatment resistance. Ongoing studies include combinations of CDK4/6 inhibitors with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors for hormone receptor-positive (HR+) breast cancers, and with selective RAF and MEK inhibitors for tumors with alterations in the mitogen activated protein kinase (MAPK) pathway such as melanoma. In particular, the combination of CDK4/6 inhibitors with endocrine therapy, such as palbociclib's recent first-line approval in combination with letrozole, is expected to transform the treatment of HR+ breast cancer. Currently, three selective CDK4/6 inhibitors have been approved or are in late-stage development: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Here we describe the current preclinical and clinical data for these novel agents and discuss combination strategies with other agents for the treatment of cancer.

Emerging findings into molecular mechanism of brain metastasis

“…Three compounds have reached the clinical stage: abemaciclib, ribociclib, and palbociclib. Recently, these drugs have been exploring the potential role in patients with estrogen receptor (ER) positive BCBM 112. A phase II study is evaluating the safety and activity of abemaciclib in hormone receptor (HR) positive BCBM and lung cancer or melanoma with BM 113.…”

Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors

“…2, 4). Downstream of both pathways, the cyclin-dependent kinases (CDK) are involved in regulation of cell cycles, DNA replication, and cell division (16). The cyclin-D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers through amplifications (CCND1, CDK4, CDK6) and loss of negative regulators (i.e., p16INK4A).…”

From chemotherapy to oncoviruses – modern methods of treatment in metastatic melanoma

“…Although treatment is combined with MEK inhibitors, the acquisition of resistance to BRAF inhibition is still proceeding; thus, prevention of resistance to vemurafenib and dabrafenib remains of special interest for modern pharmacology [1,2,22,23].…”

“…Mimo stosowania terapii skojarzonej z inhibitorami MEK poziom nabywania oporności na inhibitory BRAF nadal się zwiększa, a możliwość zapobiegania wystąpieniu oporności na wemurafenib i dabrafenib stanowi przedmiot szczególnego zainteresowania współczesnej farmakologii [1,2,22,23].…”