Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

Abstract

Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell penetrating peptide targeting matrix metalloproteinases and RGD binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule and dose dependent manner correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with non-targeted free MMAE or tumor targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell penetrating peptides.

An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer

“…Radiation could help to reduce the fibrotic microenvironment by modifying tumor permeability and vasculature, and decreasing interstitial fluid pressure, thus favoring the tumor cell uptake of drugs, such as HER3‐ADC. Interestingly, it has been suggested that radiation induces a “proteolytic switch” by modulating protease activity in the PDAC microenvironment, thus facilitating the localized delivery of therapeutics in tumors. On the other side, HER3‐ADC‐induced radiosensitization will reduce hypoxia‐mediated radioresistance in the PDAC microenvironment.…”

“…Moreover, by indirectly affecting HER2/HER3 heterodimer formation upon binding to HER3, as we previously demonstrated for the naked antibody 9F7–F11, HER3‐ADC could modulate HER2‐mediated activation of ATM/ATR signaling, CHK1 and CHK2 phosphorylation, leading to G2/M arrest . This effect could be additive with the MMAE‐mediated upregulation of DNA damage checkpoint proteins in irradiated cells . Incubation with HER3‐ADC before irradiation synergistically reduced phosphorylation of STAT3 and STAT5 in pancreatic cancer cells.…”

Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects

“…In addition, β 3 integrins are overexpressed specially in solid tumors rather than in liver and kidneys from HCT116 human colonic cancer xenografts ( Figure 5B). 29 As a specific recognition site on the ligands for β 3 , cRGD can be modified on liposomes to produce a HCT116-targeted apatinib delivery system.…”

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

“…The use of the MMAE‐ACPP conjugate 101 as a radiosensitizer for combination chemo/radiotherapy was investigated by the same group . RGD‐targeted MMAE–ACPP conjugate 101 was shown to sensitize human colorectal and pancreatic cancer cells to radiation, resulting in increased DNA damage upon dual treatment .…”