MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer

Abstract

Loss of cell-cycle control is a hallmark of cancer, which can be targeted with agents, including cyclin-dependent kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G-S cell-cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon. In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer. This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive and phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phosphoproteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive and phenotypes and prometastatic signaling. However, CDK4/6 inhibitor-resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer. .

ESR1 mutations in breast cancer

“…[80][81][82][83][84][85][86] These aberrations associated with targeted therapy resistance could be used to develop an effective treatment sequence to delay disease progression. The majority of patients with advanced or ER-positive MBC will be treated with a CDK4/6 or mTOR inhibitor in combination with ET during the course of their disease.…”

“…Indeed, several studies now demonstrate differential mechanisms of acquired resistance to either mTOR or CDK4/6 inhibitors in breast and other cancers, including upregulation of MAPK signaling in everolimus-and palbociclib-resistant models, as well as mutations in RB1, and upregulation of CDK2, CCNE1, or PDK1 in palbociclib-resistant cells. [80][81][82][83][84][85][86] These aberrations associated with targeted therapy resistance could be used to develop an effective treatment sequence to delay disease progression. Certainly, several recent and ongoing clinical trials testing investigational agents are recruiting patients who have been treated previously with mTOR or CDK4/6 inhibitors, and comparison of response between these patient populations is necessary to provide insight into whether certain patient populations benefit from sequencing of targeted therapies or are inherently resistant to therapy.…”

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

“…MTOR is a serine‐threonine kinase that placed downstream of PI3K signaling and is considered as a cardinal mediator of PI3K tumorigenic activity in cancer cells. Inhibition of mTOR sensitizes tumors to MAPK‐targeted therapies, including EGFR TKIs (Yan et al, ) and BRAF inhibitors (de Leeuw et al, ). Suppression of both mTORC1 and mTORC2 is suggested.…”

“…MAPK interacts with mediators of cancer cell proliferation located within the tumor microenvironment (TME) (Gutjahr et al, ). MAPKs and cyclin‐dependent kinases (CDKs) form a tight network of kinase complexes for regulation of cell growth and death (de Leeuw et al, ). Cancer cell proliferation may occur when regulators of MAPK pathway are mutated.…”

“…DIRAS1 and DIRAS2 are RAS‐related GTPases (bearing about 35% homogeneity with HRAS) contributed to inhibition of both PI3K/AKT and RAS/MAPK signaling pathways effective for induction of autophagy‐related cancer cell death (Sutton et al, ). The MEK inhibitor strategy is also applicable for breast cancer patients receiving inhibitors of CDK4/6 due to exhibiting MAPK‐related resistance to CDK inhibitor therapy (de Leeuw et al, ). In NRAS mutant melanoma patients receiving dual MEK/CDK4/6 inhibitors, acquired resistance to the PI3K effector S6K1 may occur that confers drug resistance (Romano et al, ), requiring convergence of MEK/CDK inhibitors with suppressors of PI3K pathway's mediators such as S6K to overcome this resistance (Sullivan, ).…”