Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models

Abstract

Tumor metastasis is a leading cause of cancer-related death. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase recruited to integrin-mediated matrix attachment sites where FAK activity is implicated in the control of cell survival, migration, and invasion. Although genetic studies support the importance of FAK activity in promoting tumor progression, it remains unclear whether pharmacological FAK inhibition prevents tumor metastasis. Here, we show that the FAK inhibitor PND-1186 blocks FAK Tyr-397 phosphorylation in vivo and exhibits anti-tumor efficacy in orthotopic breast carcinoma mouse tumor models. PND-1186 (100 mg/kg intraperitoneal, i.p.) showed promising pharmacokinetics (PK) and inhibited tumor FAK Tyr-397 phosphorylation for 12 hours. Oral administration of 150 mg/kg PND-1186 gave a more sustained PK profile verses i.p., and when given twice daily, PND-1186 significantly inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lungs. Moreover, low-level 0.5 mg/ml PND-1186 ad libitum administration in drinking water prevented oncogenic KRAS- and BRAF-stimulated MDA-MB-231 breast carcinoma tumor growth and metastasis with inhibition of tumoral FAK and p130Cas phosphorylation. Although PND-1186 was not cytotoxic to cells in adherent culture, tumors from animals receiving PND-1186 exhibited increased TUNEL staining, decreased leukocyte infiltrate and reduced tumor-associated splenomegaly. In vitro, PND-1186 reduced tumor necrosis factor-α triggered interleukin-6 cytokine expression, indicating that FAK inhibition may impact tumor progression via effects on both tumor and stromal cells. As oral administration of PND-1186 also decreased experimental tumor metastasis, PND-1186 may therefore be useful clinically to curb breast tumor progression.

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

“…High levels of both FAK and Src can be indicative of poor prognosis and tumour recurrence in a variety of cancers 5 and these data have been interpreted to suggest that inhibitors of FAK may control cancer growth and progression. Indeed several reports have shown that inhibition of FAK, often in combination with the inhibition of other targets, can suppress tumour growth and metastasis [9][10][11] . In contrast, possible negative roles for FAK in tumour progression have also been reported 12,13 .…”

“…FAK is overexpressed in many human cancer cells and has thus emerged as an anticancer target [4][5][6][7][8] . This has led to the development of FAK inhibitors although off-target effects are apparent [9][10][11] . Moreover, evidence suggests that FAK may have pleiotropic effects and some work has pointed to FAK being a negative regulator of metastasis.…”

Influence of stress on extracellular matrix and integrin biology

“…Indeed, as described above, many forms of stress may directly stimulate the function of FAK and integrin adaptors, which thus represent potential targets for chemosensitization (Ta et al, 2008;Thao le et al, 2009). This question is of special interest since the introduction of FAK inhibitors, specific Walsh et al, 2010) or not, such as some cyclooxygenase-2 inhibitors (Casanova et al, 2008).…”

Nuclear FAK: a New Mode of Gene Regulation from Cellular Adhesions

“…Increasing attention to the importance of FAK activity in triggering cancer progression has elicited, and small molecule FAK inhibitors have been extensively tested to develop anti-cancer therapeutics (Roberts et al, 2008;Stokes et al, 2011;Walsh et al, 2010).…”